Interestingly, Angiopoietin2, the ligand for Tie2, is required for the maturation of the lymphatic vessels and the formation of lymphatic valves [ 56 ]. Experiments using cultured endothelial monolayers in vitro revealed that Tie2 is upregulated and activated upon exposure of cells to shear stress [ 57 , 58 ], suggesting that Tie2 mediated signaling may be involved in regulating flow-mediated responses, and thus early stages of valve formation. In addition, lack of Akt1 leads to more specific defects in the formation of lymphatic valves in the superficial collecting vessels of the skin [ 61 ].
Concomitant with the formation of the valve leaflets, the vessel wall opposite the leaflets dilates to create a pocket on the side of each leaflet called the valve sinus. It has been demonstrated that the endothelial cells in the venous valve sinus behave differently from the ones in avalvular areas and have the ability to stretch twice as much [ 62 ].
Similar measurements have not been made in lymphatic valve sinuses; however, it is known that they are devoid of smooth muscle cells [ 14 ], which is likely to enable more extensive stretching of the vessel wall in this region. The importance of the lack of smooth muscle cells in lymphatic valves for their normal development and function was recently demonstrated. Sema3A, produced by lymphatic endothelial cells, was shown to repel smooth muscle cells expressing its receptor, NRP-1, thereby maintaining valve areas smooth muscle free [ 63 , 64 ].
Sema3A was additionally shown to regulate valve leaflet formation via interaction with NRP-1 and PlexinA1 on valve endothelial cells [ 63 ]. Other molecular regulators that may play a role in valve sinus formation or function in veins include anticoagulant markers endothelial protein receptor EPCR and thrombomodulin that are strongly expressed on venous valve leaflet and sinus, while procoagulant factors, such as VWF, present the opposite pattern [ 65 , 66 ].
Such distribution of anti- and procoagulant factors in the valve pocket favors anticoagulation, and thus is protective from thrombosis. As discussed above, the initiation of lymph flow and the resulting shear forces were suggested to define the positioning, but also the identity, of valve-forming cells [ 22 ]. This study reported upregulation of Foxc2 in vitro in lymphatic endothelial cells that were subjected to oscillatory flow, while Prox1 levels were not affected. In contrast, in another study, flow-induced downregulation of Prox1 was observed both in cultured cells in vitro and in adult lymphatic vessels in vivo [ 67 ].
In addition, Prox1 was upregulated in embryonic mesenteric lymphatic vessels that were cultured ex vivo in the absence of fluid flow [ 22 ], which could be regarded as evidence for flow-induced downregulation of Prox1 expression that normally occurs in lymphangions lymphatic vessel segments inbetween two consecutive valves.
It should be noted that the first study examined flow-regulated responses under oscillatory shear stress, which was used to mimic disturbed flow patterns in the immature lymphatic vascular plexus, while the latter study used steady laminar flow.
In addition, the shear stress levels that were applied were different. Since no measurements of shear or tangential wall stresses that are present in the developing lymphatic vessels are available, future work should investigate in more detail the precise mechanisms of valve initiation by lymph flow.
The molecular identity and morphology of valve endothelial cells. Cells on the leaflet show rounded morphology d while cells on the inflow side upstream of the valve show elongated morphology and align in flow direction e.
The free edges of the leaflets are composed of cells that show transverse orientation and are highly elongated f , arrows. I inflow, O outflow, L leaflet. While the onset of blood flow cannot provide a complete explanation for the timing of the initiation of venous valve formation that occurs postnatally, the observed molecular and morphological differences between endothelial cells in different parts of the valve suggest the involvement of flow-induced forces in modulating cellular phenotypes during later stages of valve formation.
For example, cells that are located upstream of the valve are elongated and aligned in the direction of flow, while the cells on either surface of the leaflets or lining the juxtaposed vein wall valve sinus appear to have a rounded or cuboidal morphology [ 32 ]; Fig.
Another study reported differences in the shape of cells located within different regions of the leaflet; endothelial cells on the medial surface of the valve leaflet were found to orient parallel to the long axis of the vessel, whereas those on the lateral surface aligned perpendicular to that axis [ 68 ].
Interestingly, the free ends of the valve leaflets are lined by endothelial cells that have a transverse arrangement and fusiform morphology Fig. Lymphatic valve endothelial cells acquire a similar morphology in the respective areas of the valve; for example, appearing fusiform on the free edges [ 69 ] and elongated upstream of the valve [ 22 , 24 ]. The elongated morphology of endothelial cells in venous and lymphatic vessel segments devoid of valves corroborates the observed steady attached flow conditions the cells experience, while the cuboidal shape of cells lining the leaflets suggests unsteady or oscillating shear.
Instead, valve endothelial cells are likely to experience unsteady flow patterns due to the oscillatory movement of the leaflets during equilibrium phase as well as small volume regurgitation [ 70 ], which is reflected in their cuboidal morphology. At the molecular level, differential expression of Prox1 and Ephrin-B2 was observed in vivo in cells that are exposed to different flow conditions within the valve. While Prox1 was predominantly expressed in the fusiform cells on the free edges of the valve leaflets Fig.
In summary, these observations suggest that the morphological and molecular characteristics that valve endothelial cells acquire reflect the distinct forces they experience. Consistent with this, differences in flow patterns and shear stress magnitude were previously shown to regulate gene expression and arterial-venous [ 71 , 72 ] as well as lymphatic differentiation [ 67 ].
These factors are also likely to play an important role in defining the cellular identity of valve endothelial cells. The mature venous valve leaflets are thicker at the sites of attachment to the vessel wall containing condensely packed collagen fibers; however, this deteriorates with age, thus making the valve leaflets more fragile [ 73 ]. It has also been recognized that stagnation of blood flow at the junction of valve leaflet and vessel wall can initiate microthrombus formation reviewed in [ 17 ].
Although venous valves are designed to minimize stagnation of circulating blood, secondary vortices developing deep in the pockets of the valve leaflets can create potential stagnation zones.
Such regions of unsteady flow and low velocities could cause the activation of platelets that together with red blood cells can form aggregates followed by infiltration of white blood cells through the vessel wall and initiation of responses similar to those observed in areas of trauma or atheroprone regions, while NFAT in blood vascular endothelia is regulating the activation of proinflammatory cells [ 74 — 76 ].
With ageing, a less thromboresistant phenotype present in the venous valve and possible alterations in the shear stress pattern or magnitude due to inflammation can lead to valvular lesions that can have important consequences on the normal function of the vasculature [ 77 ].
In addition, age-related fibrosis and thickening of venous valve leaflets and their decreased compliance can disrupt normal blood flow and affect the duration of blood stasis in the valve sinus, which can further abrogate the development of thrombus [ 78 , 79 ]. At the molecular level, little is known about the mechanisms regulating valve maintenance. Ephrin-B2 is additionally required for lymphatic valve maintenance [ 32 ]. In addition, loss of Cnb1 in neonatal mice led to the regression of lymphatic valve leaflets in mice, indicating a continuous requirement for Calcineurin signaling for valve maintenance [ 22 ].
The first observations on the development of lymphatic and venous valves were made nearly years ago [ 28 , 29 ], and today their importance for maintaining vascular function is well recognized, yet only recently have the molecular mechanisms that regulate valve formation begun to be elucidated.
High-resolution imaging techniques and genetic mouse models that allow targeting and visualization of venous and lymphatic valves, as well as modeling of human valve pathologies, will continue to increase our understanding of the mechanisms that regulate valve morphogenesis and contribute to diseases associated with or caused by valvular dysplasia.
Important questions of clinical relevance that still remain to be investigated in more detail are how valve development is initiated and what are the mechanisms that regulate the maintenance and normal function of valves during adulthood and aging. Finally, identification of shared and distinct pathways that regulate different types of valves should enable development of diagnostic and therapeutic approaches for specific targeting of venous and lymphatic valves.
This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author s and the source are credited.
Eleni Bazigou, Email: ku. National Center for Biotechnology Information , U. Cellular and Molecular Life Sciences. Cell Mol Life Sci. Published online Aug Eleni Bazigou 1, 2 and Taija Makinen 1. Author information Article notes Copyright and License information Disclaimer.
Corresponding author. This article has been cited by other articles in PMC. Abstract The efficient transport of blood and lymph relies on competent intraluminal valves that ensure unidirectional fluid flow through the vessels. Control of fluid flow through the vascular system: importance of valves The circulatory system is composed of the heart and the blood vessels, which distribute nutrients, hormones, gases, and metabolic waste products in the body, and the lymphatic vessels that ensure that the extravasated fluid and proteins are drained from the tissues and transported back to the blood circulation.
Fluid dynamics of the valve Recent advances in ultrasound technology have given insight into the physics of venous valve operation and have delineated the way the movement of the leaflets affects blood flow into four distinct phases of the valve cycle: opening, equilibrium, closing, and closed Fig. Open in a separate window.
Valve morphogenesis The mature venous and lymphatic valves are typically bicuspid, and are composed of two luminal leaflets that consist of two layers of endothelial cells separated by a defined connective tissue core [ 23 — 26 ]; Fig.
Onset of valve development: defining the positions While it is not fully understood how the process of valve development is initiated, it was recently shown that mechanical forces caused by fluid flow regulate the expression of key molecular regulators and cellular behaviours associated with valve-forming lymphatic endothelial cells [ 22 ]. Establishment of the valve territory The first indication of lymphatic valve development is the appearance and clustering of cells expressing elevated levels of two transcription factors, Prox1 and Foxc2, in defined positions along the vessel [ 22 , 24 , 31 , 32 ]; Figs.
Development of valve leaflets and sinus formation The development of valve leaflets is initiated by the formation of a transverse ridge on the vessel wall, which is followed by the elongation of the leaflets into the vessel lumen and formation of the commissures [ 32 ]; Fig. Valve maintenance in adults and during aging The mature venous valve leaflets are thicker at the sites of attachment to the vessel wall containing condensely packed collagen fibers; however, this deteriorates with age, thus making the valve leaflets more fragile [ 73 ].
Final remarks The first observations on the development of lymphatic and venous valves were made nearly years ago [ 28 , 29 ], and today their importance for maintaining vascular function is well recognized, yet only recently have the molecular mechanisms that regulate valve formation begun to be elucidated.
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author s and the source are credited. Contributor Information Eleni Bazigou, Email: ku.
References 1. Venous pump of the calf: a study of venous and muscular pressures. J Vasc Surg. Venous pressure dynamics of the healthy human leg: role of muscle activity, joint mobility and anthropometric factors. Together, these neural and chemical mechanisms reduce or increase blood flow in response to changing body conditions, from exercise to hydration.
Regulation of both blood flow and blood pressure is discussed in detail later in this chapter. The smooth muscle layers of the tunica media are supported by a framework of collagenous fibers that also binds the tunica media to the inner and outer tunics. Along with the collagenous fibers are large numbers of elastic fibers that appear as wavy lines in prepared slides.
Separating the tunica media from the outer tunica externa in larger arteries is the external elastic membrane also called the external elastic lamina , which also appears wavy in slides. This structure is not usually seen in smaller arteries, nor is it seen in veins. The outer tunic, the tunica externa also called the tunica adventitia , is a substantial sheath of connective tissue composed primarily of collagenous fibers.
Some bands of elastic fibers are found here as well. The tunica externa in veins also contains groups of smooth muscle fibers. This is normally the thickest tunic in veins and may be thicker than the tunica media in some larger arteries. The outer layers of the tunica externa are not distinct but rather blend with the surrounding connective tissue outside the vessel, helping to hold the vessel in relative position. If you are able to palpate some of the superficial veins on your upper limbs and try to move them, you will find that the tunica externa prevents this.
If the tunica externa did not hold the vessel in place, any movement would likely result in disruption of blood flow. An artery is a blood vessel that conducts blood away from the heart. All arteries have relatively thick walls that can withstand the high pressure of blood ejected from the heart. However, those close to the heart have the thickest walls, containing a high percentage of elastic fibers in all three of their tunics.
This type of artery is known as an elastic artery see Figure 3. Vessels larger than 10 mm in diameter are typically elastic. Their abundant elastic fibers allow them to expand, as blood pumped from the ventricles passes through them, and then to recoil after the surge has passed. If artery walls were rigid and unable to expand and recoil, their resistance to blood flow would greatly increase and blood pressure would rise to even higher levels, which would in turn require the heart to pump harder to increase the volume of blood expelled by each pump the stroke volume and maintain adequate pressure and flow.
Artery walls would have to become even thicker in response to this increased pressure. The elastic recoil of the vascular wall helps to maintain the pressure gradient that drives the blood through the arterial system. An elastic artery is also known as a conducting artery, because the large diameter of the lumen enables it to accept a large volume of blood from the heart and conduct it to smaller branches. Figure 3. Comparison of the walls of an elastic artery, a muscular artery, and an arteriole is shown.
In terms of scale, the diameter of an arteriole is measured in micrometers compared to millimeters for elastic and muscular arteries. The artery at this point is described as a muscular artery. The diameter of muscular arteries typically ranges from 0.
Their thick tunica media allows muscular arteries to play a leading role in vasoconstriction. In contrast, their decreased quantity of elastic fibers limits their ability to expand.
Fortunately, because the blood pressure has eased by the time it reaches these more distant vessels, elasticity has become less important. Rather, there is a gradual transition as the vascular tree repeatedly branches. In turn, muscular arteries branch to distribute blood to the vast network of arterioles. For this reason, a muscular artery is also known as a distributing artery. An arteriole is a very small artery that leads to a capillary. Arterioles have the same three tunics as the larger vessels, but the thickness of each is greatly diminished.
The critical endothelial lining of the tunica intima is intact. The tunica media is restricted to one or two smooth muscle cell layers in thickness. The tunica externa remains but is very thin see Figure 3.
With a lumen averaging 30 micrometers or less in diameter, arterioles are critical in slowing down—or resisting—blood flow and, thus, causing a substantial drop in blood pressure. Because of this, you may see them referred to as resistance vessels. The muscle fibers in arterioles are normally slightly contracted, causing arterioles to maintain a consistent muscle tone—in this case referred to as vascular tone—in a similar manner to the muscular tone of skeletal muscle.
In reality, all blood vessels exhibit vascular tone due to the partial contraction of smooth muscle. The importance of the arterioles is that they will be the primary site of both resistance and regulation of blood pressure. The precise diameter of the lumen of an arteriole at any given moment is determined by neural and chemical controls, and vasoconstriction and vasodilation in the arterioles are the primary mechanisms for distribution of blood flow. A capillary is a microscopic channel that supplies blood to the tissues themselves, a process called perfusion.
Exchange of gases and other substances occurs in the capillaries between the blood and the surrounding cells and their tissue fluid interstitial fluid. The diameter of a capillary lumen ranges from 5—10 micrometers; the smallest are just barely wide enough for an erythrocyte to squeeze through. Flow through capillaries is often described as microcirculation.
The wall of a capillary consists of the endothelial layer surrounded by a basement membrane with occasional smooth muscle fibers. There is some variation in wall structure: In a large capillary, several endothelial cells bordering each other may line the lumen; in a small capillary, there may be only a single cell layer that wraps around to contact itself.
For capillaries to function, their walls must be leaky, allowing substances to pass through. The most common type of capillary, the continuous capillary , is found in almost all vascularized tissues. Continuous capillaries are characterized by a complete endothelial lining with tight junctions between endothelial cells. Although a tight junction is usually impermeable and only allows for the passage of water and ions, they are often incomplete in capillaries, leaving intercellular clefts that allow for exchange of water and other very small molecules between the blood plasma and the interstitial fluid.
Substances that can pass between cells include metabolic products, such as glucose, water, and small hydrophobic molecules like gases and hormones, as well as various leukocytes.
Continuous capillaries not associated with the brain are rich in transport vesicles, contributing to either endocytosis or exocytosis. Those in the brain are part of the blood-brain barrier. Here, there are tight junctions and no intercellular clefts, plus a thick basement membrane and astrocyte extensions called end feet; these structures combine to prevent the movement of nearly all substances.
Figure 4. Other tissues, such as connective tissue, have a less abundant supply of capillaries. The epidermis of the skin and the lens and cornea of the eye completely lack a capillary network. About 5 percent of the total blood volume is in the systemic capillaries at any given time. Another 10 percent is in the lungs. Smooth muscle cells in the arterioles where they branch to form capillaries regulate blood flow from the arterioles into the capillaries.
Veins carry blood toward the heart. After blood passes through the capillaries, it enters the smallest veins, called venules.
From the venules, it flows into progressively larger and larger veins until it reaches the heart. In the pulmonary circuit, the pulmonary veins transport blood from the lungs to the left atrium of the heart. This blood has a high oxygen content because it has just been oxygenated in the lungs. The smallest blood vessels measure only five micrometers. To give you some perspective, a strand of human hair measures about 17 micrometers. But if you took all the blood vessels out of an average child and laid them out in one line, the line would stretch over 60, miles.
There are three kinds of blood vessels: arteries, veins, and capillaries. Each of these plays a very specific role in the circulation process.
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