The development of the vasculature and its extracellular matrix: a gradual process defined by sequential cellular and matrix remodeling events (2010)

EDITORIAL FOCUSThe development of the vasculature and its extracellular matrix: a gradual process defined by sequential cellular and matrix remodeling eventsGeorge E. DavisGeorge E. DavisDepartment of Medical Pharmacology and Physiology and Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine and Dalton Cardiovascular Research Center, Columbia, MissouriPublished Online:01 Aug 2010https://doi.org/10.1152/ajpheart.00525.2010This is the final version - click for previous versionMoreSectionsPDF (52 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations the molecular basis of vascular development is being elucidated because of the identification of critical growth factors, receptors, signaling pathways, and cell types that are involved (1, 2, 4, 7–10, 15). In addition to growth factor-mediated signaling, the extracellular matrix (ECM) plays a crucial role in facilitating this signaling as well as in regulating growth factor availability and activity (5, 9, 20, 21, 27). Also, the outcome of such signaling results from the recognition of a balance of positive and negative stimuli (from both growth factors and ECM) that are necessary to both form and control the developing vasculature (6, 7).A less appreciated feature of vascular development is that it represents a gradual and orchestrated sequence of events whereby different vascular beds form and then adapt to external stimuli applied by cellular interactions as well as the physical forces and signals generated by blood flow, plasma-derived factors, and hematopoietic cells circulating within the vasculature (1, 10, 14, 27). It takes time for the complex cellular organization of different blood vessels to develop and to establish appropriate cell-cell and cell-ECM interactions. In addition, time is required to form, remodel, and appropriately cross-link the vascular ECM necessary to both respond and resist the physical forces that are generated from blood flow and pressure (27). These forces vary with time during these events and gradually increase over time during fetal and postnatal development until they eventually stabilize (27). This is necessary to allow vessel development and maturation to prevent a rupture of the vasculature when these physical forces are increasingly being applied from the developing heart. Many mouse knockout animals show embryonic lethal hemorrhage phenotypes that result from vessel structural failure in small or large vessels (18). The temporal nature of these different steps, which are required to develop a functionally mature vasculature, is systematically being elucidated, but it is apparent that considerable information is still lacking toward our understanding of these critical events.In this issue of American Journal of Physiology-Heart and Circulatory Physiology, Wagenseil et al. (24) examine in a temporal manner the functional consequences of elastin deficiency using heterozygous- or homozygous-deficient elastin knockout mice (24). The authors report that the cardiovascular consequences of complete elastin deficiency are not apparent until after embryonic day (E) 18 of mouse development (24). Up to E18, there is no functional deficit despite the fact that the mouse aortas from these elastin-deficient animals showed decreased compliance (i.e., secondary to a marked loss of elasticity) and are elongated compared with wild-type aortas (24). This novel insight is particularly intriguing since it demonstrates how vessels, despite significant abnormalities, can function within a vertebrate closed circulatory system as long as the forces applied to them are low. Also, the response of the heart to these poorly compliant vessels is not yet affected because of the relatively low flow rates and pressures at this stage of cardiovascular development. However, as pressure and cardiac output forces increase from E18 to birth, the decreased arterial compliance leads to a left ventricular pressure increase to a level that is twofold greater in the homozygous elastin knockout mice compared with controls and which further results in a lethal cardiac failure phenotype (24). Of great interest is that blood pressure and cardiac output of developing mice increase in particular toward these later days of embryonic life, and this directly corresponds to increases in production of elastin and collagens (in mature arteries, they account for ∼50% of the dry weight) within the vascular wall (25–27). Interestingly, elastin and collagen synthesis within the artery wall continues to increase postnatally in mice and appear to persist until blood pressure and cardiac output have stabilized at around postnatal day 20 (27). There is also concomitant synthesis and deposition of elastin microfibril-associated proteins such as fibrillins (20, 21, 26, 27). Knockout mice reveal a requirement for fibrillin-1 in elastic fiber assembly (19). In support of this conclusion, these knockout animals die within 2 wk of birth as a result of ruptured aortic aneurysms (secondary to fragmented and thinned arterial elastic fibers) (19). Another critical and temporal step in vessel maturation is ECM cross-linking through lysyl oxidase enzymes. In particular, lysyl oxidase and lysyl oxidase like-1 have been implicated in mice because of their ability to cross-link both elastin and collagen matrixes in developing arteries (16, 27). It will be important in future studies to assess how these cross-linking enzymes affect the developing microvasculature and its ECM such as vascular basement membranes [e.g., lysyl oxidase is induced in endothelial cells (ECs) undergoing tubular morphogenesis in three-dimensional matrix environments] (3).An interesting question that is raised by the study of Wagenseil et al. (24) is how cells within the vascular wall sense these force and flow changes that eventually lead to the deficiencies apparent in the elastin knockout mice. One very interesting issue is that the number of circumferential layers of vascular smooth muscle in arteries is determined by ∼E14 of mouse development (27), which is well before the time when elastin deficiency leads to phenotypic changes leading to postnatal lethality. Also, prior work indicates that peak systolic left ventricular pressures increase from 2 to 11 mmHg from E9.5 to E14.5 of mouse development (11). Since this is the time window when the vascular smooth muscle cells accumulate around developing arteries, it is intriguing to speculate that this gradual increase in pressure (i.e., albeit at low pressures compared with later development) may be a critical stimulus for this vascular smooth muscle circumferential accumulation. However, arterial pressures dramatically increase in later postnatal life as well as postnatally where mean arterial pressures increase from postnatal days 0 to 35 from 30 to 70 mmHg (27). Thus it is these large increases in cardiac output and pressure that appear to lead to abnormal increases in blood pressure in the elastin-deficient mice that lead to cardiac failure since the elastin-deficient arteries are poorly compliant (24, 25, 27). These mutant vessels do not possess the appropriate elastic recoil to support the pulsatile flow requirements in the closed circulatory system of the mouse (27).A less recognized function of the vascular ECM, which is demonstrated in the elastin knockout mouse, is that elastin deposition appears to strongly inhibit vascular smooth muscle proliferation (12). The excess proliferation secondary to elastin deficiency leads to eventual occlusion or collapse of the aortic lumen, an event that contributes to the postnatal lethal phenotype observed in these mice (12). Interestingly, the vascular basement membrane matrix components such as laminin can inhibit EC proliferation and morphogenesis (13, 17). Also, during EC-pericyte tube coassembly events, the pericyte-derived tissue inhibitor of metalloproteinase (TIMP)-3, an ECM- and basement membrane-associated TIMP, is an inhibitor of EC tube morphogenesis in three-dimensional extracellular matrixes (6, 22) and thus contributes to vessel stabilization by interfering with further tube morphogenic events. Also, pericyte-derived TIMP-3 plays an important role in facilitating collagen type IV assembly and stability during vascular basement membrane matrix assembly secondary to EC-pericyte interactions (23). Overall, these findings suggest that one function of the developing vascular ECM is to negatively regulate vascular cell behavior by preventing the continuation of vascular morphogenic events and to facilitate a controlled process of vessel wall assembly, stabilization, and maturation.A final point concerns the question of how vascular ECM assembly (i.e., synthesis, deposition, and cross-linking) is controlled at a cellular level and how it is responsive to flow and pressure changes. Also, how is the intercellular signaling between ECs, pericytes, vascular smooth cells, and adventitial cells (in the case of the larger vessels) affected by these stimuli? In many cases of ECM assembly, it is clear that heterotypic cell-cell interactions play a crucial role (5, 23). Thus it is important to consider how the different cells within the vessel wall and within different vessel beds (with unique cellular combinations) communicate with each other to influence ECM assembly and cross-linking. For example, during early vasculogenic tube assembly in vitro and in vivo, we have recently shown that pericyte recruitment around developing EC-lined tubes is necessary to stimulate vascular basement membrane matrix assembly (23). Thus heterotypic cell-cell interactions play a major role in vascular ECM assembly events, and ECs are known to be directly responsive to the varying flows and pressures present during vascular fetal and postnatal development (10). It will be important to assess in future studies how EC-derived signals at different stages of development affect the ability of pericytes and vascular smooth muscle cells to produce, deposit, and cross-link basement membrane and interstitial matrix components to facilitate the stepwise and gradual maturation of the vasculature.GRANTSThis work was supported by National Heart, Lung, and Blood Institute Grant HL-79460 (to G. E. 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Physiol Rev 89: 957–989, 2009.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: G. E. Davis, Dept. of Medical Pharmacology and Physiology, Univ. of Missouri School of Medicine, MA415 Medical Sciences Bldg., Columbia, MO 65212 (e-mail- [email protected]missouri.edu). 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