Vascular remodelling in the embryo

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(A and B) The vascular system at 5 somite forms as loose, disconnected network. (C) At the initiation of blood flow (approximately 10 somite) the vasculature begins to be remodelled into a more efficient network. (D - F) Progressive stages of vascular remodelling, culminating in the stereotypical circulatory system seen in (F). Stages of vascular development.png
(A and B) The vascular system at 5 somite forms as loose, disconnected network. (C) At the initiation of blood flow (approximately 10 somite) the vasculature begins to be remodelled into a more efficient network. (D - F) Progressive stages of vascular remodelling, culminating in the stereotypical circulatory system seen in (F).

Vascular remodelling is a process which occurs when an immature heart begins contracting, pushing fluid through the early vasculature. The process typically begins at day 22, and continues to the tenth week of human embryogenesis. This first passage of fluid initiates a signal cascade and cell movement based on physical cues including shear stress and circumferential stress, which is necessary for the remodelling of the vascular network, arterial-venous identity, angiogenesis, and the regulation of genes through mechanotransduction. This embryonic process is necessary for the future stability of the mature vascular network. [2]

Contents

Vasculogenesis is the initial establishment of the components of the blood vessel network, or vascular tree. This is dictated by genetic factors and has no inherent function other than to lay down the preliminary outline of the circulatory system. Once fluid flow begins, biomechanical and hemodynamic inputs are applied to the system set up by vasculogenesis, and the active remodelling process can begin.

Physical cues such as pressure, velocity, flow patterns, and shear stress are known to act on the vascular network in a number of ways, including branching morphogenesis, enlargement of vessels in high-flow areas, angiogenesis, and the development of vein valves. The mechanotransduction of these physical cues to endothelial and smooth muscle cells in the vascular wall can also trigger the promotion or repression of certain genes which are responsible for vasodilation, cell alignment, and other shear stress-mitigating factors. This relationship between genetics and environment is not clearly understood, but researchers are attempting to clarify it by combining reliable genetic techniques, such as genetically ablated model organisms and tissues, with new technologies developed to measure and track flow patterns, velocity profiles, and pressure fluctuations in vivo . [2]

Both in vivo study and modelling are necessary tools to understand this complex process. Vascular remodelling is pertinent to wound healing and proper integration of tissue grafting and organ donations. Promoting an active remodelling process in some cases could help patients recover faster and retain functional use of donated tissues. However, outside of wound healing, chronic vascular remodelling in the adult is often symptomatic of cardiovascular disease. Thus, increased understanding of this biomedical phenomenon could aid in the development of therapeutics or preventative measures to combat diseases such as atherosclerosis.

Historical view

Over 100 years ago, Thoma observed that increases in local blood flow cause widening of the vessel diameter and he even went so far as to postulate that blood flow might be responsible for the growth and development of blood vessels. [3] Subsequently, Chapman in 1918 discovered that removing a chick embryo's heart disrupted the remodelling process, but the initial vessel patterns laid down by vasculogenesis remained undisturbed. Next, in 1926 Murray proposed that vessel diameter was proportional to the amount of shear stress at the vessel wall; that is, that vessels actively adapted to flow patterns based on physical cues from the environment, such as shear stress.

The chemical basis of morphogenesis," written in 1952 by mathematician and computer scientist Alan Turing advocated for various biological models based on molecular diffusion of nutrients. [4] However, a diffusive model of vascular development would seem to fall short of the complexity of capillary beds and the interwoven network of arteries and veins. [4] [5] In 2000, Fleury proposed that instead of diffusive molecules bearing responsibility for the branching morphogenesis of the vascular tree, a long-range morphogen may be implicated. In this model, a traveling pressure wave would act upon the vasculature via shear stress to rearrange branches into the lowest-energy configuration by widening vessels carrying increased blood flow and rearranging networks upon the initiation of fluid flow. [4] [6] It is known that mechanical forces can have a dramatic impact on the morphology and complexity of the vascular tree. [5] [6] However, these forces have comparably little impact on the diffusion of nutrients, and it therefore seems unlikely that acquisition of nutrients and oxygen plays a significant role in embryonic vascular remodelling. [5]

It is now widely accepted[ weasel words ][ by whom? ] that vascular remodelling in the embryo is a process distinct from vasculogenesis; however these two processes are inextricably linked. Vasculogenesis occurs prior to vascular remodelling, but is a necessary step in the development of the blood vessel network and has implications on the identification of vessels as either arterial or venous. Once contraction of the heart begins, vascular remodelling progresses via the interplay of forces resulting from biomechanical cues and fluid dynamics, which are translated by mechanotransduction to changes at cellular and genetic levels.

Vasculogenesis

Human embryo at approximately 30 days, showing development of various structures including the yolk sac. From Gray's anatomy. Gray23.png
Human embryo at approximately 30 days, showing development of various structures including the yolk sac. From Gray's anatomy.

Vasculogenesis is the formation of early vasculature, which is laid down by genetic factors. [7] Structures called blood islands form in the mesoderm layer of the yolk sac by cellular differentiation of hemangioblasts into endothelial and red blood cells. [7] Next, the capillary plexus forms as endothelial cells migrate outward from blood islands and form a random network of continuous strands. [7] These strands then undergo a process called lumenization, the spontaneous rearrangement of endothelial cells from a solid cord into a hollow tube. [8]

Inside the embryo, the dorsal aorta forms and eventually connect the heart to the capillary plexus of the yolk sac. [7] This forms a closed-loop system of rigid endothelial tubing. Even this early in the process of vasculogenesis, before the onset of blood flow, sections of the tube system may express ephrins or neuropilins, genetic markers of arterial or venous identities, respectively. [7] These identities are still somewhat flexible, but the initial characterization is important to the embryonic remodelling process. [2]

Angiogenesis also contributes to the complexity of the initial network; spouting endothelial buds form by an extrusion-like process which is prompted by the expression of vascular endothelial growth factor (VEGF). [8] These endothelial buds grow away from the parent vessel to form smaller, daughter vessels reaching into new territory. [8] Intussusception, the phenomenon of a single tube splitting to form two branching tubes, also contributes to angiogenesis. [8] Angiogenesis is generally responsible for colonizing individual organ systems with blood vessels, whereas vasculogenesis lays down the initial pipelines of the network. [9] Angiogenesis is also known to occur during vascular remodelling. [9]

Arterial-venous identity

In this anatomical image from Gray's Anatomy, it can be seen that the cardiac vein develops in close proximity to the arterial network, and in early embryos, sections may switch identities from arterial to venous vessels. Gray491.png
In this anatomical image from Gray's Anatomy, it can be seen that the cardiac vein develops in close proximity to the arterial network, and in early embryos, sections may switch identities from arterial to venous vessels.

The classification of angioblasts into arterial- or venous-identified cells is essential to form the proper branching morphology. [2] Arterial segments of the early vasculature express ephrinB2 and DLL4 whereas venous segments express neuropilin-2 and EPHB4; this is believed to assist in guidance of flow from arterial-venous sections of the loop. [2] However, mechanical cues provided by the heart's first contractions are still necessary for complete remodelling. [2]

The first event of biomechanical-driven hierarchal remodelling occurs just after the onset of heart beat, when the vitelline artery forms by the fusion of several smaller capillaries. Subsequently, side branches may disconnect from the main artery and reattach to the venous network, effectively changing their identity. [10] This is thought[ by whom? ] to be due to the high luminal pressure in the arterial lines, which prevents reattachment of the branches back onto arterial vessels. [10] This also prevents the formation of shunts between the two components of the network. [5] Moyon et al. showed that arterial endothelial cells could become venous and vice versa. [11] They grafted sections of quail endothelial tubing which had previously expressed arterial markers onto chick veins (or vice versa), showcasing the plasticity of the system. Reversing flow patterns in arteries and/or veins can also have the same effect, although it is unclear whether this is due to differences in physical or chemical properties of venous vs. arterial flow (i.e. pressure profile and oxygen tension). [10]

Another example of the fluidity of arterial-venous identity is that of the intersomitic vessel. At early stages, this vessel is connected to the aorta, making it part of the arterial network. [2] However, sprouts from the cardiac vein may fuse with the intersomitic vessel, which slowly disconnects from the aorta and becomes a vein. [2] This process is not fully understood, but may occur out of a need to balance mechanical forces such as pressure and perfusion. [2]

Arterial-venous identity in the early stages of embryonic vascular remodelling is flexible, with arterial segments often being recycled to venous lines and the physical structure and genetic markers of segments being actively remodelled along with the network itself. [10] This indicates that the system as a whole exhibits a degree of plasticity which allows it to be shaped by transitory flow patterns and hemodynamic signals, however genetic factors do play a role in the initial specification of vessel identity. [2]

Biomechanics

Once the heart begins to beat, mechanical forces start acting upon the early vascular system, which rapidly expands and reorganizes to serve tissue metabolism. [9] In embryos devoid of blood flow, endothelial cells retain an undifferentiated morphology similar to angioblasts (compared to flattened epithelial cells found in mature vasculature). [2] Once the heart begins beating, the morphology and behaviour of endothelial cells change. [2] [12] By changing the heart rate, the heart can also control perfusion or pressure acting upon the system in order to trigger sprouting of new vessels. [2] In turn, new vessel sprouting is balanced by the expansion of other embryo tissues, which compress blood vessels as they grow. [5] The equilibrium of these forces plays a major role in vascular remodelling, but although the angiogenic mechanisms required to trigger the sprouting of new vessels have been studied, little is known about the remodelling processes required to curb the growth of unnecessary branches. [2]

Examples of biomechanical forces acting on connective tissue. From Gray's Anatomy. Cartilage forces.jpg
Examples of biomechanical forces acting on connective tissue. From Gray's Anatomy.

As blood perfuses the system, it exerts shear and pressure forces on the vessel walls. At the same time, tissue growth outside the cardiovascular system pushes back on the outside of the vessel walls. These forces must be balanced to obtain an efficient energy state for low-cost delivery of nutrients and oxygen to all tissues of the embryo body. [2] When growth of the yolk sac (external tissue) is constrained, the balance between vascular forces and tissue forces is shifted and some vascular branches may be disconnected or diminished during the remodelling process because they are unable to forge new paths through the compressed tissue. [2] In general, the stiffness and resistance of these tissues dictates the degree to which they can be deformed and the way in which biomechanical forces can affect them. [2]

The development of the vascular network is self-organized at each point in the tissue due to the balance between compressive forces of tissue expansion and circumferential stretch of the vessel walls. [5] Over time, this means that migrating lines become straight rather than curving; this is akin to imagining two moving boundaries pushing on each other. [5] Straight vessels are usually parallel to isopressure lines because the boundaries have acted to equilibriate pressure gradients. [5] In addition, vessel direction tends to follow the direction of the normal to the steepest stress gradient. [5]

Additionally, biomechanic forces inside embryonic vessels have important remodelling effects. Pressure fluctuations lead to stress and strain fluctuations, which can "train" the vessels to bear loads later in the organism's development. [9] The fusion of several small vessels can also generate large vessels in areas of the vascular tree where blood pressure and flow rate are larger. [10] Murray's law is a relation between the radius of parent vessels to the radius of branches which holds true for the circulatory system. This outlines the balance between the lowest resistance to flow presented by vessel size (because large-diameter vessels exhibit a low pressure drop) and the maintenance of the blood itself as a living tissue which cannot diffuse ad infinitum. [2] Therefore, complex branching is required to supply blood to organ systems, as diffusion alone cannot be responsible for this.[ according to whom? ][ original research? ]

Biomechanics act on the vascular network connections as well. Luminal pressure has been shown to direct the recycling of vessel segments to high-pressure areas, [5] and govern the disconnection of vessel segments from arterial lines and reattachment to venous lines in order to shape the network. [7] This type of vessel breakage may even be indirectly responsible for the development of some organ systems and the evolution of larger organisms, as without detachment and migration, large masses of tissue in the embryo would remain disconnected from the blood supply. [5] Once vessels break away from the parent artery, they may also undergo angiogenesis to infest tissues distal to the rest of the network. [2]

Fluid dynamics

Representation of laminar flow between two walls. The pressure gradient at the fluid boundary layer (green) is transmitted to the walls by shear stress. Separating-two-plates-pressure-gradient-and-shear-stress.png
Representation of laminar flow between two walls. The pressure gradient at the fluid boundary layer (green) is transmitted to the walls by shear stress.

Fluid dynamics also plays an important role in vascular remodelling. The shear stress applied to vessel walls is proportional to the viscosity and flow patterns of the fluid. Disturbed flow patterns can promote the formation of valves and increasing pressure can affect the radial growth of vessels. [9] The primitive heart within the first few days of contraction is best described as a peristaltic pump, however after three days the flow becomes pulsatile. [9] Pulsatile flow plays an important role in vascular remodelling, as flow patterns can affect the mechanotransduction of stress to endothelial cells. [7] [13]

Dimensionless relations such as the Reynolds number and Womersley number can be used to describe flow in early vasculature. [7] The low Reynolds number present in all early vessels means that flow can be considered creeping and laminar. [7] A low Womersley number means that viscous effects dominate flow structure and that boundary layers can be considered to be non-existent. [7] This allows the fluid dynamic computations to rest upon certain assumptions which simplify the mathematics.[ original research? ]

During the first stages of embryonic vascular remodelling, high-velocity flow is not present solely in large-diameter vessels, but this corrects itself due to the effects of vascular remodelling over the first two days of blood flow. [14] It is known[ by whom? ] that embryonic vessels respond to increases in pressure by increasing the diameter of the vessel. [9] Due to the absence of smooth muscle cells and the glycocalyx, which provide elastic support in adult vessels, blood vessels in the developing embryo are much more resistant to flow. [7] This means that increases in flow or pressure can only be answered by rapid, semi-permanent expansion of the vessel diameter, rather than by more gradual stretch and expansion experienced in adult blood vessels. [7]

Rearranging the Laplace and Poiseuille relations suggests that radial growth occurs as a result of circumferential stretch and circumferential growth occurs as a result of shear stress. [9] Shear stress is proportional to the speed inside the vessel as well as the pressure drop between two fixed points on the vessel wall. [5] The precise mechanism of vessel remodelling is believed to be high stress on the inner wall of the vessel which can induce growth, which heads toward uniform compressive and tensile stress on both sides of the vessel wall. [9] Generally, it has been found[ by whom? ] that circumferential residual stress is compressive and tensile, indicating that inner layers of the endothelial tube grow more than outer layers. [15]

Mechanotransduction and genetic regulation

A feedback model of genetic regulation. In this case the input is a physical force and the feedback can be positive or negative depending on the value of B. Ideal feedback model.svg
A feedback model of genetic regulation. In this case the input is a physical force and the feedback can be positive or negative depending on the value of B.

The mechanism by which different types of flow patterns and other physical cues have different effects on vascular remodelling in the embryo is called mechanotransduction. Turbulent flow, which is commonplace in the developing vasculature, plays a role in the formation of cardiac valves which prevent backflows associated with turbulence. [16] It has also been shown that heterogeneous flow patterns in large vessels can create asymmetry, perhaps by preferentially activating genes such as PITX2 on one side of the vessel, or perhaps by inducing circumferential stretch on one side, promoting regression on the other side. [6] [17] Laminar flow also has genetic effects, such as reducing apoptosis, inhibiting proliferation, aligning cells in direction of flow, and regulating many cell signalling factors. [7] Mechanotransduction may act either by positive or negative feedback loops, which may activate or repress certain genes to respond to the physical stress or strain placed on the vessel.

The cell "reads" flow patterns through integrin sensing, receptors which provide a mechanical link between the extracellular matrix and the actin cytoskeleton. This mechanism dictates how a cell will respond to flow patterns and can mediate cell adhesion, which is especially relevant to the sprouting of new vessels. [2] Through the process of mechanotransduction, shear stress can regulate the expression of many different genes. The following examples have been studied in the context of vascular remodelling by biomechanics:

Different flow patterns and their duration can elicit very different responses based on the shear-stress-regulated genes. [7] Both genetic regulation and physical forces are responsible for the process of embryonic vascular remodelling, yet these factors are rarely studied in tandem., [2] [7]

In vivo study

The main difficulty in the in vivo study of embryonic vascular remodelling has been to separate the effects of physical cues from the delivery of nutrients, oxygen, and other signalling factors which may have an effect on vascular remodelling. [7] Previous work has involved control of blood viscosity in early cardiovascular flow, such as preventing the entry of red blood cells into blood plasma, thereby lowering viscosity and associated shear stresses. [18] Starch can also be injected into the blood stream in order to increase viscosity and shear stress. [18] Studies have shown that vascular remodelling in the embryo proceeds without the presence of erythrocytes, which are responsible for oxygen delivery. [18] Therefore, vascular remodelling does not depend on the presence of oxygen and in fact occurs before perfused tissues require oxygen delivery. [7] However, it is still unknown whether or not other nutrients or genetic factors may have promotional effects on vascular remodelling. [18]

Measurement of parabolic velocity profiles in live embryo vessels indicate that vessel walls are exposed to levels of laminar and shear stress which can have a bioactive effect. [14] Shear stress on embryonic mouse and chicken vasculature ranges between 1 – 5 dyn/cm2. [14] This can be measured by either cutting sections of blood vessels and observing the angle of the opening, which bends to relieve residual stress, [15] or by measuring the hematocrit present in blood vessels and calculating the apparent viscosity of the fluid. [7]

Due to the difficulties involved with imaging live embryo development and accurately measuring small values of viscosity, pressure, velocity, and flow direction, increased importance has been placed on developing an accurate model of this process. This way, an effective method for studying these effects in vitro may be found.[ according to whom? ]

Modelling

A number of models have been proposed to describe fluid effects on the vascular remodelling in the embryo. One point which is often missed[ according to whom? ] in these analogies is the fact that the process occurs within a living system; dead end can break off and reattach elsewhere, branches close and open at junctions or form valves, and vessels are extremely deformable, able to quickly adapt to new conditions and form new pathways. Theoretically, the formation of the vascular tree can be thought of in terms of percolation theory. The network of tubes arises randomly and will eventually establish a path between two separate and unconnected points. Once some critical number of sprouting tubes have migrated into a previously unoccupied area, a path called a fractal can be established between these two points. [8] Fractals are biologically useful constructions, as they rely on an infinite increase in surface area, which in biological terms translates to a vast increase in transport efficiency of nutrients and wastes. [8] The fractal path is flexible; if one connection is broken, another forms to re-establish the path. [8] This is a useful illustration of how the vascular tree forms, although it cannot be used as a model. The diffusion-limited aggregation model has given simulated results which are closest in comparison to vascular trees in vivo. This model suggests that vascular growth occurs along a gradient of shear stress at the vessel wall, which results in the growth of vessel radii. [20] Diffusion-limited aggregation proposes that an aggregate grows by the fusion of random walkers, which themselves walk along a pressure gradient. [5] Random walk is simply a probability-based version of the diffusion equation. [5] Thus, in applying this model to the vascular tree, small, resistant vessels must be replaced with large, conducting vessels in order to balance the pressure across the entire system. [5] This model yields a structure which is more random at the tips than in the major lines, which is related to the fact that Laplacian formulations are stable when speed is negative with respect to pressure gradient. [5] In major lines, this is always so, but in small sprouts the speed fluctuates around 0, leading to unstable, random behaviour. [5]

Another large component of the remodelling process is the disconnection of branched vessels, which then migrate to distal areas in order to supply blood homogeneously. [5] Branching morphogenesis has been found to follow the dielectric breakdown model, in that only the vessels with sufficient flow will enlarge, while others will close off. [5] At locations inside the vessel where two tube split off from one, one arm of the split is likely to close, detach, and migrate towards the venous line, where it will re-attach. The result of the closure of a branch is that flow increases and becomes less turbulent in the main line, while blood also begins to flow towards areas which are lacking. [5] Which branch will close depends on the flow rate, direction, and branching angle; in general, a branching angle of 75° or more will necessitate the closing of the smaller branch. [5]

Thus, several important parameters of vascular remodelling can be described using the combined models of diffusion-limited aggregation and dielectric breakdown: the probability that a branch will close off (plasticity of vessel splitting), that a vessel will reconnect to the venous line (plasticity of sprout regrowth), shrinkage resistance of sprouting tips (a balance between external compression and internal shear stress), and the ratio of external tissue growth to internal vessel expansion. However, this model does not take into effect the diffusion of oxygen or signalling factors which may play a role in embryonic vascular remodelling. [5] These models consistently reproduce most aspects of the vasculature seen in vivo in several different specialized cases. [5]

Application to study of disease progression

Neuropilin 2 expression in (A) blood vessels, (B) carcinoma tissue, (C and D) breast carcinoma tissue with co-localized staining for neuropilin 2 and CXCR4, a chemokine receptor. Neuropilin 2 is a known marker for venous blood vessels, indicating the vascularization of the tumour. Neuropilin-2 (Nrp2) expression in normal breast and breast carcinoma tissue.jpg
Neuropilin 2 expression in (A) blood vessels, (B) carcinoma tissue, (C and D) breast carcinoma tissue with co-localized staining for neuropilin 2 and CXCR4, a chemokine receptor. Neuropilin 2 is a known marker for venous blood vessels, indicating the vascularization of the tumour.

Vascular remodelling in non-embryonic tissues is considered to be symptomatic of disease progression. Cardiovascular disease remains one of the most common causes of death globally [22] and is often associated with the blockage or stenosis of blood vessels, which can have dramatic biomechanical effects. In acute and chronic remodelling, the increase in shear stress due to the decreased diameter of a blocked vessel can cause vasodilation, thereby restoring typical shear stress levels. [6] [23] However, dilation also leads to increased blood flow through the vessel, which can result in hyperaemia, affect physiological regulatory actions downstream of the afflicted vessel, and place increased pressure on atherosclerotic plaques which may lead to rupture. [6] Blockage of blood vessels is currently treated by surgically inserting stents to force vessel diameters open and restore normal blood flow. By understanding the implication of increased shear stress on homeostatic regulators, alternative, less-invasive methods may be developed to treat vessel blockage.

The growth of tumours often results in reactivation of blood vessel growth and vascular remodelling in order to perfuse the new tissue with blood and sustain its proliferation. [2] Tumour growth has been shown to be self-organizing and to behave more similarly to embryonic tissues than to adult tissues. [24] As well, vessel growth and flow dynamics in tumours are thought[ by whom? ] to recapitulate the vessel growth in developing embryos. [2] In this sense, embryonic vascular remodelling can be considered a model of the same pathways which are activated in tumour growth, and increased understanding of these pathways can lead to novel therapeutics which may inhibit tumour formation.[ original research? ]

Conversely, angiogenesis and vascular remodelling is an important aspect of wound healing and the long-term stability of tissue grafts. [2] When blood flow is disrupted, angiogenesis provides sprouting vessels which migrate into deprived tissues and restore perfusion. Thus, the study of vascular remodelling may also provide important insight into the development of new techniques to improve wound healing and benefit the integration of tissues from transplants by lowering the incidence of rejection.[ according to whom? ]

Related Research Articles

<span class="mw-page-title-main">Artery</span> Blood vessels that carry blood away from the heart

An artery is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in the pulmonary circulation that carry blood to the lungs for oxygenation, and the umbilical arteries in the fetal circulation that carry deoxygenated blood to the placenta.

<span class="mw-page-title-main">Blood vessel</span> Tubular structure of the circulatory system which transports blood

Blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away from the tissues. Blood vessels are needed to sustain life, because all of the body's tissues rely on their functionality.

<span class="mw-page-title-main">Capillary</span> Smallest type of blood vessel

A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the site of the exchange of many substances from the surrounding interstitial fluid, and they convey blood from the smallest branches of the arteries (arterioles) to those of the veins (venules). Other substances which cross capillaries include water, oxygen, carbon dioxide, urea, glucose, uric acid, lactic acid and creatinine. Lymph capillaries connect with larger lymph vessels to drain lymphatic fluid collected in microcirculation.

<span class="mw-page-title-main">Angiogenesis</span> Blood vessel formation, when new vessels emerge from existing vessels

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

<span class="mw-page-title-main">Endothelium</span> Layer of cells that lining inner surface of blood vessels

The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

Vascular resistance is the resistance that must be overcome to push blood through the circulatory system and create blood flow. The resistance offered by the systemic circulation is known as the systemic vascular resistance (SVR) or may sometimes be called by the older term total peripheral resistance (TPR), while the resistance offered by the pulmonary circulation is known as the pulmonary vascular resistance (PVR). Systemic vascular resistance is used in calculations of blood pressure, blood flow, and cardiac function. Vasoconstriction increases SVR, whereas vasodilation decreases SVR.

<span class="mw-page-title-main">Glycocalyx</span> Viscous, carbohydrate rich layer at the outermost periphery of a cell.

The glycocalyx, also known as the pericellular matrix and sometime cell coat, is a glycoprotein and glycolipid covering that surrounds the cell membranes of bacteria, epithelial cells, and other cells. It was described in a review article in 1970.

Vascular endothelial growth factor, originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

Vasculogenesis is the process of blood vessel formation, occurring by a de novo production of endothelial cells. It is sometimes paired with angiogenesis, as the first stage of the formation of the vascular network, closely followed by angiogenesis.

Arteriogenesis refers to an increase in the diameter of existing arterial vessels.

Neovascularization is the natural formation of new blood vessels, usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circulation in response to local poor perfusion or ischemia.

<span class="mw-page-title-main">Endothelial stem cell</span> Stem cell in bone marrow that gives rise to endothelial cells

Endothelial stem cells (ESCs) are one of three types of stem cells found in bone marrow. They are multipotent, which describes the ability to give rise to many cell types, whereas a pluripotent stem cell can give rise to all types. ESCs have the characteristic properties of a stem cell: self-renewal and differentiation. These parent stem cells, ESCs, give rise to progenitor cells, which are intermediate stem cells that lose potency. Progenitor stem cells are committed to differentiating along a particular cell developmental pathway. ESCs will eventually produce endothelial cells (ECs), which create the thin-walled endothelium that lines the inner surface of blood vessels and lymphatic vessels. The lymphatic vessels include things such as arteries and veins. Endothelial cells can be found throughout the whole vascular system and they also play a vital role in the movement of white blood cells

In medicine, collateralization, also vessel collateralization and blood vessel collateralization, is the growth of a blood vessel or several blood vessels that serve the same end organ or vascular bed as another blood vessel that cannot adequately supply that end organ or vascular bed sufficiently.

<span class="mw-page-title-main">Ephrin receptor</span> Protein family

Eph receptors are a group of receptors that are activated in response to binding with Eph receptor-interacting proteins (Ephrins). Ephs form the largest known subfamily of receptor tyrosine kinases (RTKs). Both Eph receptors and their corresponding ephrin ligands are membrane-bound proteins that require direct cell-cell interactions for Eph receptor activation. Eph/ephrin signaling has been implicated in the regulation of a host of processes critical to embryonic development including axon guidance, formation of tissue boundaries, cell migration, and segmentation. Additionally, Eph/ephrin signaling has been identified to play a critical role in the maintenance of several processes during adulthood including long-term potentiation, angiogenesis, and stem cell differentiation and cancer.

Endothelial progenitor cell is a term that has been applied to multiple different cell types that play roles in the regeneration of the endothelial lining of blood vessels. Outgrowth endothelial cells are an EPC subtype committed to endothelial cell formation. Despite the history and controversy, the EPC in all its forms remains a promising target of regenerative medicine research.

<span class="mw-page-title-main">Vascular endothelial growth factor A</span> Protein involved in blood vessel growth

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

Lymph sacs are a part of the development of the lymphatic system, known as lymphangiogenesis. The lymph sacs are precursors of the lymph vessels. These sacs develop through the processes of vasculogenesis and angiogenesis. However, there is evidence of both of these processes in different organisms. In mice, it is thought that the lymphatic components form through an angiogenic process. But, there is evidence from bird embryos that gives rise to the idea that lymphatic vessels arise in the embryos through a vasculogenesis-like process from the lymphangioblastic endothelial precursor cells.

Endothelial activation is a proinflammatory and procoagulant state of the endothelial cells lining the lumen of blood vessels. It is most characterized by an increase in interactions with white blood cells (leukocytes), and it is associated with the early states of atherosclerosis and sepsis, among others. It is also implicated in the formation of deep vein thrombosis. As a result of activation, enthothelium releases Weibel–Palade bodies.

<span class="mw-page-title-main">Coalescent angiogenesis</span> Process of blood vessel formation

Angiogenesis is the process of the formation of new blood vessels from pre-existing vascular structures, which is needed for oxygenation of - and providing nutrients to - expanding tissue. Angiogenesis takes place through different modes of action. Coalescent angiogenesis is a mode of angiogenesis where vessels coalesce or fuse to increase blood circulation. This process transforms an inefficient net structure into a more efficient treelike structure. It is the opposite of intussusceptive angiogenesis, which is where vessels split to form new vessels.

References

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  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Jones, Elizabeth A. V.; le Noble, Ferdinand; Eichmann, Anne (2006). "What Determines Blood Vessel Structure? Genetic Prespecification vs. Hemodynamics". Physiology. 21 (6): 388–395. doi:10.1152/physiol.00020.2006. ISSN   1548-9213.
  3. ↑ Thoma, R. (1893). Untersuchungen ü ber die Histogenese und Histo- mechanik des 1186 Gefä ßsystems. Stuttgart, Germany: Ferdinand Enke
  4. 1 2 3 Fleury, V. (2000). Branching morphogenesis in a reaction-diffusion model. Physical Review E 61: 4156 – 4160. PMID   11088210
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Nguyen, Thi-Hanh; Eichmann, Anne; Le Noble, Ferdinand; Fleury, Vincent (2006-06-14). "Dynamics of vascular branching morphogenesis: The effect of blood and tissue flow". Physical Review E. 73 (6): 061907. doi:10.1103/PhysRevE.73.061907. ISSN   1539-3755.
  6. 1 2 3 4 5 Koller, Akos; Kaley, Gabor (1996). "Shear Stress Dependent Regulation of Vascular Resistance in Health and Disease: Role of Endothelium". Endothelium. 4 (4): 247–272. doi:10.3109/10623329609024701. ISSN   1062-3329.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Jones, Elizabeth A. V. (2010). "Mechanotransduction and blood fluid dynamics in developing blood vessels". The Canadian Journal of Chemical Engineering. 88 (2): 136–143. doi:10.1002/cjce.20290. ISSN   0008-4034.
  8. 1 2 3 4 5 6 7 Forgacs, G. and Newman, S.A. (2005). Biological Physics of the Developing Embryo. Cambridge, UK: Cambridge University Press. ISBN   978-0-521-78337-8
  9. 1 2 3 4 5 6 7 8 9 Taber, Larry A. (2001). "Biomechanics of Cardiovascular Development". Annual Review of Biomedical Engineering. 3 (1): 1–25. doi:10.1146/annurev.bioeng.3.1.1. ISSN   1523-9829.
  10. 1 2 3 4 5 le Noble, Ferdinand; Moyon, Delphine; Pardanaud, Luc; Yuan, Li; Djonov, Valentin; Matthijsen, Robert; Bréant, Christiane; Fleury, Vincent; Eichmann, Anne (2004-01-15). "Flow regulates arterial-venous differentiation in the chick embryo yolk sac". Development. 131 (2): 361–375. doi:10.1242/dev.00929. ISSN   1477-9129.
  11. ↑ Moyon, D. et al. (September, 2001). Plasticity of endothelial cells during arterial-venous differentiation in the avian embryo. Development 128: 3359 – 3370. PMID   11546752
  12. ↑ Wakimoto, Koji; et al. (2000). "Targeted Disruption of Na+/Ca2+ Exchanger Gene Leads to Cardiomyocyte Apoptosis and Defects in Heartbeat". Journal of Biological Chemistry. 275 (47): 36991–36998. doi:10.1074/jbc.M004035200.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ↑ Buschmann, I. et al. (April, 2010). Pulsatile shear and Gja5 modulate arterial identity and remodelling events during flow-driven arteriogenesis. Development 137: 2187–2196. PMID   20530546
  14. 1 2 3 Jones, E.A.V.; Baron, M.H.; Fraser, S.E.; Dickinson, M.E. (2004). "Measuring hemodynamic changes during mammalian development". American Journal of Physiology-Heart and Circulatory Physiology. 287 (4): H1561–H1569. doi:10.1152/ajpheart.00081.2004. ISSN   0363-6135.
  15. 1 2 Chuong, C.J. and Fung, Y.C. (1986). On residual stress in arteries. Journal of Biomechanics 108: 189 – 192. PMID   3079517
  16. ↑ Hove, Jay R.; Köster, Reinhard W.; Forouhar, Arian S.; Acevedo-Bolton, Gabriel; Fraser, Scott E.; Gharib, Morteza (2003). "Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis". Nature. 421 (6919): 172–177. doi:10.1038/nature01282. ISSN   0028-0836.
  17. ↑ Yashiro, Kenta; Shiratori, Hidetaka; Hamada, Hiroshi (2007). "Haemodynamics determined by a genetic programme govern asymmetric development of the aortic arch". Nature. 450 (7167): 285–288. doi:10.1038/nature06254. ISSN   0028-0836.
  18. 1 2 3 4 5 Lucitti, Jennifer L.; et al. (2007-09-15). "Vascular remodeling of the mouse yolk sac requires hemodynamic force". Development. 134 (18): 3317–3326. doi:10.1242/dev.02883. ISSN   1477-9129. PMC   4260474 . PMID   17720695.
  19. ↑ Castier, Yves; Ramkhelawon, Bhama; Riou, Stéphanie; Tedgui, Alain; Lehoux, Stephanie (2009). "Role of NF-κB in Flow-Induced Vascular Remodeling". Antioxidants & Redox Signaling. 11 (7): 1641–1649. doi:10.1089/ars.2008.2393. ISSN   1523-0864.
  20. ↑ Fleury, Vincent; Schwartz, Laurent (1999). "Diffusion limited aggregation from shear stress as a simple model of vasculogenesis". Fractals. 07 (01): 33–39. doi:10.1142/S0218348X99000050. ISSN   0218-348X.
  21. ↑ Yasuoka, Hironao; Kodama, Rieko; Tsujimoto, Masahiko; Yoshidome, Katsuhide; Akamatsu, Hiroki; Nakahara, Masaaki; Inagaki, Michiya; Sanke, Tokio; Nakamura, Yasushi (2009). "Neuropilin-2 expression in breast cancer: correlation with lymph node metastasis, poor prognosis, and regulation of CXCR4 expression". BMC Cancer. 9 (1). doi: 10.1186/1471-2407-9-220 . ISSN   1471-2407. PMC   2719661 . PMID   19580679.
  22. ↑ Mendis, S. et al. (2011). Global Atlas on Cardiovascular Disease Prevention and Control. World Health Organization: Geneva. ISBN   978-92-4-156437-3
  23. ↑ Castier, Yves; Brandes, Ralf P.; Leseche, Guy; Tedgui, Alain; Lehoux, Stéphanie (2005-09-16). "p47phox-Dependent NADPH Oxidase Regulates Flow-Induced Vascular Remodeling". Circulation Research. 97 (6): 533–540. doi:10.1161/01.RES.0000181759.63239.21. ISSN   0009-7330.
  24. ↑ Dormann, S. and Deutsch, A. (2002). Modelling of self-organized avascular tumour growth with a hybrid cellular automaton. In Silico Biology 2: 393 – 406. PMID   12542422
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