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Blood vessels deliver nutrients and other molecules, as well as blood and immune cells, to all tissues in our body. The vascular network branches in a hierarchical fashion and is organized spatially to provide adequate nutrients to the cells of all organs and supporting structures by diffusion and convection. The walls of vessels are composed of endothelial cells and mural cells, which are embedded in an extracellular matrix (ECM; ). The origin, number, type and organization of mural cells, the composition of the associated matrix, and the connection between the vascular system and the nervous system depend on the location of the vessel and its function. To reach this level of complex organization, the immature vascular network, formed by vasculogenesis or angiogenesis, must mature at the level of the vessel wall as well as at the network level. Maturation of the wall involves recruitment of mural cells, development of the surrounding matrix and elastic laminae, and organ-specific specialization of endothelial cells (ECs), mural cells and matrix (such as interendothelial junctions, fenestrations, apical-basal polarity, surface receptor ). Maturation of the network involves optimal patterning of the network by branching, expanding and pruning to meet local demands (). Here we will focus on our current understanding of the molecular and cellular players involved in blood vessel maturation. Recent studies have provided important new discoveries about the ways in which these players govern vessel maturation during embryogenesis and during physiological processes, as well as failures of maturation in various pathologies. Although key questions remain unanswered for both blood and lymphatic vessel development, these discoveries could lead to new approaches for both therapeutic angiogenesis and antiangiogenic therapyVessel maturation in embryonic developmentDuring development, the vasculature forms by both vasculogenesis and angiogenesis. In either case, the components of the vessel wall—endothelial cells, mural cells and matrix—originate from multiple sources (). In its simplest embodiment, vascular development can be thought of as involving the following processes: branching, re and specialization. The timing of most of these processes overlaps, allowing the vasculature to evolve seamlessly to maturation. Furthermore, each of the molecules involved has multiple functions in the development of a mature vascular network (; for a detailed description of each molecule, see
online and refs. ).Formation of immature vasculature. During embryonic development, the nascent vascular network is formed by vasculogenesis (de novo vessel formation from angioblasts or stem cells) as well as angiogenesis (sprouting, bridging and intussusceptive growth from existing vessels). Vascular endothelial growth factor (VEGF) signaling is an important aspect of this process. VEGFA not only initiates vessel formation, but also sets in motion a chain of molecular and cellular events that ultimately lead to a mature vascular network. In brief, CD31+CD34+ VEGF receptor (VEGFR)-2-positive angioblasts form a vascular plexus that gives rise to the dorsal aorta, the cardinal vein and the embryonic stems of yolk sac arteries and veins. Sprouting angiogenesis is presumably facilitated by hypoxia, which upregulates expression of a number of genes involved in vessel formation, patterning and maturation, including nitric oxide synthase, VEGF, and angiopoietin-2. Existing vessels dilate in response to nitric oxide, a product of nitric oxide synthase, and become leaky in response to VEGF. The basement membrane and ECM dissolve in response to activation of proteases (such as matrix metalloproteinase (MMP)2, MMP3 and MMP9) and suppression of protease inhibitors (such as tissue inhibitor of metalloproteinase-2). Plasma proteins leaked from these nascent vessels serve as a provisional matrix. ECs migrate through interactions between integrins and the matrix, and proliferate in response to VEGF and other endothelial cell mitogens. Angiopoietin (Ang)2 facilitates sprout formation in the presence of VEGF. The sprouts anastomose to form vascular loops and networks.Stabilization of immature vasculature. The nascent vessels are stabilized by recruiting mural cells and by generating ECM. At least four molecular pathways are involved in regulating this process: platelet-derived growth factor (PDGF) B?PDGF receptor (PDGFR)-; sphingosine-1-phosphate-1 (S1P1)?endothelial differentiation sphingolipid G-protein-coupled receptor-1 (EDG1)); Ang1-Tie2; and transforming growth factor (TGF)-. PDGFB is secreted by ECs, presumably in response to VEGF, and facilitates recruitment of mural cells. Although PDGFB is expressed by a number of cells, including ECs and mural cells, signaling through PDGFR-, which is expressed on mural cells, is responsible for their proliferation and migration during vascular maturation. Compelling support for this hypothesis comes from studies of Pdgfb knockout mice, which undergo embryonic lethality, lack pericytes in certain vessels and exhibit microvascular aneurysm ( online).The similarity between the phenotypes of Pdgfb-Pdgfrb and Edg1 knockout mice (failure of mural cells to migrate to blood vessels) indicates that signaling through the EDG1 receptor, which is expressed by mural cells, is another key pathway for mural cell recruitment. EDG1 receptor signaling may occur downstream of PDGF signaling, although this hypothesis has recently been questioned. Alternatively, the lack of EDG1 may alter the EC matrix production or EC?mural cell interaction, and interfere with vessel maturation. Targeted deletion of Gi13, a molecule downstream of EDG3, also yields a Edg1 knockout phenotype, and both PDGFB- and PDGFR--deficient mice exhibit markedly reduced expression of RGS5, a GTPase-activating protein for Gi, on their vascular plexi and small arteries ( online).Also critical for vessel formation and stabilization are the Tie receptors, Tie1 and Tie2, and two ligands for Tie2, Ang1 and Ang2 (refs. ,). Main sources of Ang1 and Ang2 are the mural cells and ECs, respectively. Ang1 is known to stabilize nascent vessels and make them leak-resistant, presumably by facilitating communication between ECs and mural cells. Notably, in the absence of mural cells, recombinant Ang1 restored a hierarchical order of the larger vessels, and rescued edema and hemorrhage, in the growing retinal vasculature of mouse neonates. Thus, the mechanism of vessel maturation by Ang1 is far from clear. The role of Ang2 appears to be contextual. In the absence of VEGF, Ang2 acts as an antagonist of Ang1 and destabilizes vessels, ultimately leading to vessel regression. In the presence of VEGF, Ang2 facilitates vascular sprouting.TGF-1, a multifunctional cytokine, promotes vessel maturation by stimulating ECM production and by inducing differentiation of mesenchymal cells to mural cells. It is expressed in a number of cell types, including ECs and mural cells and, depending on the context and concentration, is both pro- and antiangiogenic. Studies of knockout mice also underscore the importance of TGF-1, its receptors (RI, RII and endoglin) and the downstream signaling molecules (ALK1, Smad5) in the initial phases of angiogenesis and vessel maturation ( online). Recent in vitro studies indicate that the TGF-1?ALK1 pathway induces ECs and fibroblasts to express Id1, a protein required for proliferation and migration. On the other hand, the TGF-1?ALK5 pathway induces the plasminogen activator inhibitor (PAI)1 in endothelial cells. PAI1 promotes vessel maturation by preventing degradation of the provisional matrix around the nascent vessel. Thus, the ratio of TGF- signals through ALK1 versus ALK5 is likely to determine the pro- or antiangiogenic effect of TGF-. One molecule that may orchestrate this balance is endoglin, a TGF-?binding protein (type III receptor). Endoglin knockout mice exhibit normal vasculogenesis but undergo embryonic lethality as a result of defective vascular remodeling and smooth muscle cell (SMC) differentiation. Similarly, mutations in endoglin and ALK1 have been linked to human vascular disorders (hereditary hemorrhagic telengiectasia (HHT)-1 and HHT-2, respectively). Collectively, these studies indicate that TGF-1, ALK1 and endoglin are positive regulators of endothelial cell migration and proliferation, whereas the TGF-1?ALK5 pathway is a positive regulator of vessel maturation.Branching, remodeling and pruning of vasculature. The final or optimal pattern of the vascular network for an organ is determined by the growth, branching, remodeling and pruning of its different segments. In addition to using signaling pathways that are involved in regulating branching in the nervous system (such as ephrins and neuropilins), various basement membrane and ECM components provide cues for these processes by regulating the proliferation, survival, migration and differentiation of ECs and mural cells (see accompanying review in Nature Reviews Cancer).The matrix serves as a store for various growth factors and proenzymes involved in vessel development. The control of basement membrane and ECM degradation by proteases (such as MMP2, MMP3, MMP9, and urokinase plasminogen activator) and their inhibitors (such as tissue inhibitors of metalloproteinases and PAI1) influences EC and mural-cell migration. These proteases also release various proangiogenic growth factors (such as VEGF and basic fibroblast growth factor (FGF)) that are sequestered in the matrix, and generate antiangiogenic molecules by cleaving plasma proteins (such as angiostatin from plasminogen), matrix molecules (such as tumstatin from collagen type IV), or the proteases themselves (such as PEX from MMP2). The spatial and temporal concentration profiles of these growth factors and protein fragments, determined by their transport and binding to the matrix, presumably affect the branching pattern of vessels by regulating proliferation and apoptosis of endothelial cells and mural cells ( online).Advances in our understanding of integrins provide clues about the ways in which different matrix components influence EC survival and migration. For example, both pharmacological and genetic approaches indicate that fibronectin, its receptor 51, collagen I, and collagen receptors 11 and 21, are proangiogenic. Similarly, both pharmacologic and genetic approaches show that Tsp1 and Tsp2 are powerful inhibitors of angiogenesis and can exert this effect through intergrins and proteases. Paradoxically, unlike the pharmacologic interventions, the disruption of genes encoding v3 and v5 (integrin receptors for fibronectin, vitronectin, fibrinogen, osteopontin, thrombospondin, endostatin and von Willebrand factor) does not block angiogenesis. Also, unlike administration of endostatin (a fragment of the basement-membrane collagen XVIII), disruption of the gene encoding collagen XVIII does not affect angiogenesis. Further investigations are needed to provide a unified framework for the complex role of cell-matrix interactions in vessel formation and maturation.Vessel specialization. The least understood step in the maturation process is the tissue- and organ-specific specialization of wall and network structure ( and ). This process includes arterio-venous determination, formation of homotypic and heterotypic junctions, and EC differentiation to form organ-specific capillary structures. Based on the observation that the veins grafted on the arterial side of the vascular network develop an arterial wall structure, it was initially assumed that flow (shear stress) was the determinant of arterio-venous specification. However, recent findings from ephrin knockout mice indicate that arterio-venous specification is genetically determined, and that an arterio-capillary-venous arrangement is completed before the heart starts pumping blood ( online). Compelling evidence from knockout mice and zebrafish, as well as analysis of two human diseases, Alagille syndrome and cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), indicate that the Notch pathway determines the arterial-venous fate of ECs, possibly by committing angioblasts to these two lineages. As the capillary plexus forms, bidirectional ephrin and ephrin receptor signaling repels the arterial and venous sides, and thus guides branching. Arterial differentiation may then be further promoted by TGF-1?Alk1 signaling, and venous differentiation suppressed by Notch signaling. Continued arterial growth is then promoted by VEGF164?VEGFR2?neuropilin (NRP)1 signaling. Lastly, expansion of larger arteries and veins occurs by acquisition of additional layers of mural cells, ECM and elastic laminae to provide the requisite viscoelastic properties and neural control.Homotypic and heterotypic junctions, including EC?EC, EC?mural cell, and gap junctions, facilitate cell-to-cell communication and regulate vessel permeability. Vascular endothelial cadherin is an important component of EC-EC junctions, whereas neural (N)-cadherin facilitates EC?mural cell communication. Gap junctions made of connexins (such as Cx37, Cx40 and Cx43) also facilitate communication between ECs, and between ECs and perivascular cells. CD31, present on ECs and most leukocytes, is involved in angiogenesis as well as leukocyte extravasation through EC?EC junctions. Tight junctions made of occludins, claudins and zona occludens (ZO1, ZO2 and ZO3) contribute to the blood-tissue barrier in the brain and retinal capillaries. Finally, VEGF and endocrine gland?derived (EG)-VEGF induce fenestrations in ECs. How the local mechanical or biochemical microenvironment controls the formation of cell-cell junctions and leads to continuous, discontinuous, and fenestrated capillaries in different organs to meet local demands is yet to be determined.Formation and maturation of lymphatic networkThe vascular network in our body consists of not only blood vessels, but also of lymphatic vessels. The lymphatic vessels collect fluid, macromolecules, and immune cells that have extravasated from blood into the tissue. They also provide an important route of metastasis. Our understanding of the formation and maturation of lymphatic networks, however, is in its infancy in comparison to our understanding of blood vessels. Embryonic lymphatic vessels primarily originate from blood vessels. Lymphatic ECs originate from the cardinal vein during embryonic development. Molecular approaches have confirmed this notion in recent years, and have suggested additional sources of lymphatic ECs which include lymphangioblasts and lymphatic endothelial precursor cells. In the early embryo, ECs of the cardinal vein express lymphatic vascular endothelial receptor (LYVE)1 and VEGFR3. An as-yet-unknown signal triggers the expression of the homeobox gene Prox1, which commits these cells to the lymphatic lineage. These LYVE1-VEGFR3-Prox1?positive cells begin to sprout. Expression of secondary lymphoid cytokine and upregulation of VEGFR3 signals the formation of the lymphatic vessels. The Syk-SLP76 pathway triggers the separation of the embryonic lymphatic and blood vascular networks.Targeted deletion of Ang2 suggests that it is involved in the maturation and patterning of lymphatic vessels, and Ang1 can rescue this function of Ang2. Targeted deletion of NRP2 suggests that it is required for the formation of lymphatic capillaries but not large lymphatic vessels ( online). How the nascent lymphatics mature, develop valves, anchor to surrounding matrix and form a functional lymphatic network is still enigmatic. A recent mouse model of lymphangiogenesis suggests that interstitial fluid flow guides the formation and pattern of lymphatic network. With the development of new animal models and the identification of new molecular players, our understanding of lymphangiogenesis and lymphatic maturation will advance rapidly.Vessel maturation in physiological angiogenesisAngiogenesis and the maturation of resulting vessels contribute to a number of physiological processes, including wound healing, reproductive cycling and ocular maturation. It is reasonable to assume that molecules involved in vessel formation and maturation during embryonic development are also involved in the postnatal period, but their precise role is not known because most knockout mice ( online) die pre- or perinatally. Based on antibody blocking studies and gain-of-function studies, it appears that the spatio-temporal pattern of expression and concentration of various molecules involved may differ between the pre- and postnatal period. Changes in the local metabolic and mechanical microenvironment, such as the presence of hypoxia, low pH, abnormal hydrostatic pressure or shear stress, also profoundly influence the formation, maturation and remodeling of small and large vessels as a part of normal physiological processes. Information about the way in which these triggers alter the transcriptional profile of ECs and mural cells is beginning to shed light on the molecular pathways that underlie vascular remodeling and maturation in health and disease. (Further discussion of these pathways is beyond the scope of this review). Wound healing provides an example of the general principles involved in physiological vessel maturation.After wound or tissue injury, activated platelets stimulate vessel growth by releasing a number of proteins, including TGF- and PDGF. Formation of this granulation tissue is facilitated by chemotaxis of neutrophils, monocytes, fibroblasts, myofibroblasts and ECs. Fibroblasts initially secrete collagen III, followed by collagen I; once enough collagen is generated to allow wound closure, its synthesis is stopped. In the early stages of wound healing, a large number of immature vessels form. Later, some are pruned and the remaining vessels mature. Formation of the lymphatic network follows that of the vascular network.In cutaneous wound healing, intravital and immunohistochemical studies indicate that VEGF and Ang2 expression increase initially, and subsequently decrease to baseline levels after a stable vascular network is formed. A slight and transient decline in Ang1 expression is observed soon after wound formation, and a second decline is observed after vessel maturation. During this process, sources of VEGF include keratinocytes, monocytes and fibroblast-like cells, whereas Ang1 is produced largely by pericytes. These data are consistent with the hypothesis that VEGF and Ang2 induce vessel formation, whereas Ang1 is involved in vessel stabilization by mediating EC?mural cell interactions. Surprisingly, the angiogenesis inhibitor endostatin, a collagen-XVIII fragment, impairs vessel maturation during wound healing without altering the expression of VEGF, Ang1 and Ang2 (ref. ). Endostatin-treated wounds show a significant reduction in the number of functional vessels, as well as a lower expression of matrix molecules (collagens I and III and fibronectin). The reduced connective tissue density may improve the quality of the healed wound. This finding indicates that excessively large numbers of newly formed vessels may not be required for normal healing. In patients with diabetes, wound healing may be impaired due to deregulation of VEGF, PDGF, FGF and other growth factors. Further studies in conditional knockout mice are likely to provide mechanistic insights into physiological vessel formation and maturation.Abnormal maturation in pathological angiogenesisA large number of human diseases are characterized by abnormal vessels (see accompanying review in this issue). Here we will illustrate the general concepts using tumors as an example, as an abnormal vasculature is a hallmark of solid tumors (). Tumor vessels are organized in a chaotic fashion and do not follow the hierarchical branching pattern of normal vascular networks (). Whereas normal tissue maintains an equilibrium between vascular growth and cellular demands—no cells are farther from the nearest blood vessel than the distance the nutrients can diffuse before being completely consumed—the lack of such an equilibrium in tumors results in avascular, hypoxic voids of many sizes. The size and number of such voids, as measured by the fractal dimension, correspond to invasion percolation (a stochastic process in which a network expands around rando see ).
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第一句Blood vessels deliver nutrients and other molecules, as well as blood and immune cells, to all tissues in our body.血管传递营养，其他分子，血液，免疫细胞到我们体内的所有组织。
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血管提供营养物质和其他分子，以及血液和免疫细胞，到我们的身体的所有组织。血管网络的分支机构和分层方式组织空间提供足够的营养，所有器官的细胞和支撑结构，通过扩散和对流。是由血管壁的内皮细胞和壁画细胞，在细胞外基质（ECM;图1）嵌入式。壁细胞的来源，数量，类型和组织，相关的矩阵组成，血管系统和神经系统之间的连接取决于船只和其功能的位置。为了达到这个复杂的组织，不成熟的血管网络形成，血管形成或血管生成水平，必须在血管壁的水平，以及在网络层面的成熟。墙上的成熟涉及招聘壁细胞，周围基质和弹性椎板发展，内皮细胞和器官特异性专业化（ECS），壁画细胞和基质（如interendothelial路口，开窗术，根尖 - 基底极性，表面的受体和脚过程中，图1）。网络的成熟涉及分枝，扩大和修剪，以满足当地需求（图2）网络的最佳图案。在这里，我们将重点放在我们目前所了解的参与血管成熟的分子和细胞的球员。最近的研究提供了有关的方法，使这些球员管在胚胎发育过程中和生理过程的血管成熟的重要的新发现，以及各种病症的成熟的失败。虽然血液和淋巴管发展的关键问题仍然没有答案，这些发现可能导致新的方法的治疗性血管生成和抗血管生成therapy1血管在胚胎developmentDuring发展成熟，血管生成和血管生成的血管形式。在这两种情况下，血管壁的内皮细胞，壁画细胞和基质来自多个来源（1盒）的组成部分。在其最简单的体现，血管的发展可以被认为涉及以下过程：形成稳定;分支，重塑和修剪;和专业化。大多数这些过程重叠的时机，使血管无缝发展成熟。此外，每个分子参与多种功能，在一个成熟的血管网（框2的每一个分子的详细描述，请参阅补充表1网上和文献3,4,5,6,7）发展。形成不成熟的血管。胚胎发育过程中，新生的血管网是由血管生成（从头angioblasts或干细胞血管形成）以及血管生成（发芽，架桥，从现有的船只intussusceptive增长）。血管内皮生长因子（VEGF）信号是一个重要方面，这process8 9。 VEGFA不仅启动舰艇编队，而且还套在运动中的分子和细胞事件，最终导致一个成熟的血管network3，4,5,6,7链。在简短，CD31 + CD34 +细胞血管内皮生长因子受体（VEGFR）- 2阳性angioblasts形成一个血管丛，引起背主动脉，大是大非静脉和卵黄囊动脉和静脉的胚胎茎。大概是促进发芽血管生成缺氧，上调参与血管形成，图案和成熟，包括一氧化氮合酶，血管内皮生长因子，血管生成素-2基因的表达。现有的血管扩张反应一氧化氮，一氧化氮合酶的产品，并成为以血管内皮生长因子的漏水。基底膜和ECM溶解在反应激活的蛋白酶（如基质金属蛋白酶（MMP）2，MMP3和MMP9）和抑制蛋白酶抑制剂（如组织MMP - 2的抑制剂）。从这些新生的血管泄漏的血浆蛋白作为临时矩阵。内皮细胞迁移，通过整合与基体之间的相互作用，以及VEGF等血管内皮细胞有丝分裂原增殖。血管生成素（ANG）2，有利于发芽形成的血管内皮生长因子的存在。豆芽吻合形成血管的循环和不成熟的血管networks.Stabilization。招聘壁画细胞产生流脑的新生血管稳定。至少有四个分子途径参与调节这一过程：血小板衍生生长因子（PDGF）乙PDGF受体（PDGFR） - 鞘氨醇1 - 磷酸- 1（S1P1）的内皮细胞的分化鞘脂G蛋白偶联受体？ EDG1（1））; ANG1 -受体Tie2;和转化生长因子（TGF）-. PDGFB精英，大概是在回应血管内皮生长因子的分泌，并有利于招募壁画细胞。虽然PDGFB表达的细胞的数量，包括内皮细胞和壁画细胞信号通过，PDGFR -，这是壁画细胞中表达，其增殖和迁移血管maturation10期间负责。这一假说的令人信服的支持来自PDGFB基因敲除小鼠的研究，在某些船只接受胚胎的杀伤力，缺乏周细胞，并表现出微血管瘤（补充表1在线）PDGFB - Pdgfrb的表型和Edg1敲除小鼠（失败之间的相似性。壁画细胞迁移到血管）表??示，信号通过，这是壁画细胞中表达，EDG1受体是另一个关键壁画细胞recruitment11途径。 EDG1受体信号可能发生的PDGF信号的下游，虽然这一假说最近被questioned12。另外，EDG1缺乏可能会改变生产或EC欧共体矩阵？壁画细胞相互作用，干扰船只成熟。针对性删除Gi13，EDG3下游的分子，也产生了Edg1淘汰赛表型，并都PDGFB和PDGFR - 缺陷小鼠表现出对他们的血管丛和小arteries13的RGS5表达明显减少，为GI GTP酶激活蛋白， （补充表1在线）。血管的形成和稳定的关键是领带的受体，TIE1和受体Tie2，受体Tie2，Ang1和Ang2的（注释4,14）两个配体。 Ang1和Ang2的主要来源是壁画细胞和内皮细胞，分别。 ANG1被称为稳定新生血管和使他们防漏，大概是促进在内皮细胞和壁画细胞之间的沟通。值得注意的是，在壁细胞的情况下，重组ANG1恢复了较大的船只的等级秩序，并救出鼠标neonates15日益增长的视网膜血管水肿和出血，。因此，由ANG1船只成熟的机制还远未明朗。 Ang2的作用似乎是上下文。 ANG1拮抗剂Ang2的行为，破坏血管，在血管内皮生长因子的情况下，最终导致船舶回归。 Ang2的血管内皮生长因子的存在，有利于血管sprouting.TGF - 1，一种多功能细胞因子，促进船只通过刺激ECM生产和壁画cells16，17间质细胞诱导分化成熟。它表达的细胞类型，包括内皮细胞和壁细胞的背景和浓度而定，是亲和antiangiogenic18。基因敲除小鼠的研究也强调重要性，TGF - 1及其受体（RI，RII和endoglin）和血管生成和血管maturation16的初始阶段，19（补充表1网上）的下游信号分子（ALK1，Smad5）。最近在体外研究表明，TGF -β1？ALK1通路诱导内皮细胞和成纤维细胞表达ID1，增殖和迁移所需的一种蛋白质。另一方面，TGF -β1 ALK5通路诱导内皮细胞纤溶酶原激活物抑制剂（PAI）的1。 PAI1促进血管成熟，防止周围新生血管的临时矩阵退化。因此，TGF -β信号通过ALK1与ALK5的比率是可能确定的亲或抗血管生成作用TGF -β。协调这种平衡的一个分子，可能是endoglin，一个TGF -β结合蛋白（Ⅲ型受体）。 Endoglin基因敲除小鼠表现出正常的血管生成，但作为一个有缺陷的血管重塑和平滑肌细胞（SMC）的分化的结果进行胚胎杀伤力。同样，在endoglin和ALK1基因突变已被证实与人类血管疾病（遗传性出血性telengiectasia（HHT）-1和HHT - 2，分别）。总的来说，这些研究表明，TGF - 1，ALK1和endoglin是积极的监管机构的内皮细胞迁移和增殖，而TGF -β1？ALK5途径是正调节船只maturation20.Branching，重塑和血管修剪。器官的血管网的最终或最佳模式是由增长，分支，其不同细分市场的重塑和修剪。除了使用信号途径参与调节神经系统（如ephrins和neuropilins）4,21,22，各种基底膜和ECM组件提供了这些过程的线索，通过调节细胞增殖，存活，迁移和分化分支ECS和壁画细胞（见所附自然评论Cancer23审查）。矩阵作为存储为各种生长因子和血管发育涉及酶原。基底膜和ECM降解蛋白酶（如MMP2，MMP3，MMP9，尿激酶型纤溶酶原激活剂）及其抑制剂（如组织抑制剂金属蛋白酶和PAI1）控制的影响欧共体和壁画细胞迁移。这些蛋白酶也释放各种血管形成的生长因子（如血管内皮生长因子和碱性成纤维细胞生长因子（FGF））被隔离在基质中，和裂解血浆蛋白（如血管抑素从纤维蛋白溶酶原），基质分子（如肿瘤抑素产生抗血管生成的分子IV型胶原），或蛋白酶（如从MMP2 PEX）。这些生长因子和蛋白质碎片的空间和时间的浓度分布，其运输和有约束力的矩阵的决定，大概是通过调节内皮细胞和壁细胞（补充表1网上）的增殖和凋亡的影响船只的分枝格局。进展我们整合的理解，提供有关线索的方式，在不同的基质成分的影响EC生存和迁移。例如，药理和遗传方法表明，纤维连接蛋白，51及其受体Ⅰ型胶原，和胶原蛋白受体11和21，是促进血管形成的的。同样，药物和遗传方法显示，TSP1和Tsp2强大的血管生成抑制剂，可以通过intergrins和proteases24施加影响。奇怪的是，不像药物的干预措施，V3和V5（vitronectin，纤维连接蛋白，纤维蛋白原，骨桥蛋白，凝血酶，血管内皮抑制素和血管性血友病因子的整合素受体）编码基因的干扰不阻止angiogenesis25，26。此外，与血管内皮抑制素（基底膜胶原第十八片段），编码基因的胶原第十八中断管理，不影响angiogenesis27。需要进一步调查，以提供一个统一的血管形成的细胞 - 基质相互作用和maturation23，26,28。容器的专业化的复杂作用框架。了解最少的步骤是在成熟过程中的组织和器官特异性的墙壁和专业化的网络结构（图1和2）29。这个过程包括动静脉的决心，形成同型和异型路口，以及欧共体分化形成器官特异性毛细管结构。观察动脉血管网嫁接静脉动脉壁结构的基础上，它最初是假设流量（剪切应力），动静脉规范的决定性因素。但是最近的研究成果，从ephrin基因敲除小鼠表明，动静脉规范是由基因决定的，和动静脉毛细血管安排之前完成心脏开始输送血液（补充表1网上）。从基因敲除小鼠和斑马鱼，以及两个人类疾病，Alagille综合征和脑皮层下梗死和白质脑病（CADASIL）的常染色体显性动脉分析的令人信服的证据，表明Notch途径的决定，可能是由动脉，静脉命运的ECS这两个lineages7承诺angioblasts。由于毛细血管丛的形式，双向ephrin和ephrin受体信号排斥的动脉和静脉的两侧，从而指南分支。动脉分化可能进一步促进TGF - 1？ALK1信号，静脉分化抑制Notch信号。续动脉增长，然后推动VEGF164 VEGFR2的？neuropilin（NRP）1信号。最后，购置附加层壁画细胞发生较大的动脉和静脉扩张，ECM和弹性椎板提供必要的粘弹性能和神经control.Homotypic和异型路口，包括体壁画细胞和缝隙连接，促进细胞与细胞的沟通和调节血管通透性。血管内皮细胞钙粘蛋白是EC -欧共体路口的一个重要组成部分，而神经（N）- cadherin的促进欧共体？壁画细胞的沟通。间隙连接蛋白（如Cx37，Cx40和Cx43）路口，也方便之间的内皮细胞，内皮细胞和血管周围细胞之间的沟通。目前，ECS和最白细胞CD31，是参与血管生成以及通过欧共体欧共体路口白细胞外渗。 occludins，claudins和透明occludens（ZO1，ZO2和ZO3）紧密连接在大脑和视网膜毛细血管的血液组织屏障作出贡献。最后，血管内皮生长因子和内分泌腺？派生（EG）的血管内皮生长因子诱导内皮开窗术。当地的机械或生化微环境如何控制的细胞与细胞间的路口，并导致连续，断续的形成，在不同的器官，以满足当地需求和孔毛细血管是有待determined.Formation和淋巴networkThe血管网络的成熟，在我们的身体组成不仅血管，也有淋巴管。淋巴管收集液，大分子，与免疫细胞从血液进入组织淤血。他们还提供了一个重要的转移途径。然而，淋巴网络的形成和成熟的理解是比较我们了解血管处于起步阶段。胚胎淋巴管主要来自血管。淋巴管内皮细胞来源于胚胎发育过程中的大是大非静脉。分子的方法近年来已证实了这一概念，并有其他来源的建议，其中包括lymphangioblasts31和淋巴管内皮细胞的前体cells32淋巴ECs30。在早期胚胎中，内皮细胞表达淋巴的大是大非静脉血管内皮细胞受体（LYVE）1和VEGFR3。一个未知的信号触发的同源盒基因Prox1，犯这些细胞淋巴谱系的表达。这些LYVE1 VEGFR3 Prox1？阳性细胞开始萌芽。次级淋巴因子的表达和淋巴管形成的VEGFR3信号的上调。 Syk的SLP76通路触发的胚胎淋巴和血液血管Ang2的networks33.Targeted删除的分离表明，它是在参与的成熟和淋巴管，并ANG1图案可以拯救这个Ang2的功能。 NRP2删除的有针对性的建议，这是需要形成的毛细淋巴管，但没有大的淋巴管（补充表1网上）。新生的淋巴管成熟，发展阀门，锚周围基质，形成一个功能性淋巴网络仍然是高深莫测的。最近的淋巴管的小鼠模型表明，间质流体流动引导的形成和淋巴network34格局。淋巴管和淋巴管成熟的认识有了新的动物模型的发展和确定新的分子球员，将提前在生理angiogenesisAngiogenesis rapidly.Vessel成熟，导致血管的成熟的生理过程，包括伤口愈合，生殖骑自行车和眼部成熟。它是合理的假设，在胚胎发育过程中血管的形成和成熟所涉及的分子也参与在产后时期，但其确切的作用是不知道，因为大多数的基因敲除小鼠（补充表1在线）前或围产期死亡。抗体阻断研究和增益的功能研究的基础上，似乎之间的产前和产后期间的表达和参与的各种分子浓度的时空格局可能会有所不同。在局部代谢和机械微环境的变化，如缺氧，低pH值，静水压力不正常或剪应力的存在，也深刻地影响正常生理过程的一部分小型和大型船舶的形成，成熟和重塑。有关信息的方式在这些触发改变的内皮细胞和壁画细胞的转录概况开始棚上的分子途径，在健康和疾病的血管重构和成熟的基础。 （进一步讨论这些途径是本次审查的范围之外）35,36,37,38。伤口愈合提供了一个涉及生理船只maturation.After伤口或组织损伤的一般原则，例如，活化血小板刺激血管生长，所释放出的蛋白质，包括TGF -β和PDGF39。这个肉芽组织的形成，促进趋化中性粒细胞，单核细胞，成纤维细胞，肌纤维母细胞和ECs40。我的成纤维细胞的初步分泌胶原Ⅲ，胶原一旦足够的胶原蛋白生成，让伤口缝合，其合成停止。在伤口愈合的早期阶段，不成熟的血管形成的大量。后来，一些修剪，其余船只mature41。淋巴管网的形成，血管network34.In皮肤伤口愈合，活体和免疫组化研究表明，VEGF和Ang2表达的增加最初，并随后下降到基线水平后形成一个稳定的血管网络。 ANG1表达一个轻微和短暂的下降是观察伤口形成后不久，和第二次下降后观察血管maturation42。在这个过程中，血管内皮生长因子的来源包括角质细胞，单核细胞和成纤维样细胞，而主要是由周细胞产生ANG1。这些数据与假设一致，VEGF和Ang2诱导血管的形成，而ANG1稳定船舶参与调解欧共体？壁画细胞间的相互作用。令人惊讶的是，血管生成抑制剂血管内皮抑制素，胶原蛋白第十八片段，损害血管成熟，在伤口愈合没有改变血管内皮生长因子，Ang1和Ang2的（参见42）的表达。血管内皮抑制素治疗的伤口显示在功能船只的数量显着减少，以及低表达的基质分子（胶原蛋白Ⅰ，Ⅲ和纤维连接蛋白）。减少结缔组织密度可提高愈合伤口的质量。这一发现表明，无法满足正常愈合所需。在糖尿病患者，伤口愈合可能受到损害，由于放松管制的血管内皮生长因子，PDGF，FGF和其他增长factors43。条件基因敲除小鼠的进一步研究，可能是由异常血管的特点（见所附检讨在这issue44）在人类疾病的病理angiogenesisA大量maturation.Abnormal成熟的机械见解。在这里我们将说明使用为例，肿瘤的一般概念，是一种异常的血管是实体肿瘤的标志（图2b）45,46。肿瘤血管组织在一个混乱的方式和不按正常的血管网络的层次分支模式（图3A，B）。而正常组织保持血管生长和细胞之间的平衡要求没有细胞是从更远的距离比最近的血管的营养物质扩散前被完全consumed47缺乏这种平衡肿瘤导致股骨头缺血，缺氧的许多空隙大小。这样的空隙，分形维数计算的规模和数量的，符合入侵渗流（一个随机的过程中，网络扩展周围随意放置的障碍;见专栏3）48。
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