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Vasculature Growth

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Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems

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Abstract

Vasculogenesis, an embryological process, defines the formation of capillary plexi from endothelial precursor cells. A primitive vascular network is built via the assembly of angioblasts. Initial patterning of embryonic vascular network is independent of hemodynamic forces. The onset of blood circulation contributes to vasculature remodeling.

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Notes

  1. 1.

    E.g., Hairy enhancer of Split [HES]-related transcriptional regulators HRT1 and HRT2 promotes arterial differentiation; nuclear receptor NR2f2 favors venous differentiation [886].

  2. 2.

    Haptotaxis corresponds to the adhesion gradient associated with the concentration of the constituents of the support medium, i.e., gradient in extracellular matrix density.

  3. 3.

    Tumors are hypoxic at some stage because of high oxygen consumption and inadequate blood supply. In response to hypoxia, tumor cells secrete angiogenic factors. Angiogenesis promotes tumor progression and metastasis.

  4. 4.

    In addition to mesenchymal stem cells, basophils, eosinophils, neutrophils, T lymphocytes, NK cells, and monocytes use CCL7 chemoattractant.

  5. 5.

    Vascular network development is regulated by local interactions between vascular cells and hemodynamic conditions.

  6. 6.

    Intussusception corresponds to pillar formation for capillary genesis. It is observed in the rapidly expanding postnatal lung capillary bed. The shape of these pillars is maintained by endothelial cells and pericytes. The pillars can grow in size and number. They can also merge to form folds and new vascular branches. There are 3 modes of intussusception [1176]: intussusceptive microvascular growth, arborization, and branching remodeling. Intussusceptive microvascular growth is characterized by insertion of transluminal pillars, which induces a rapid expansion of the capillary plexus. Vessels are generated from the capillary plexus by intussusceptive arborization by perpendicular pillar formation in rows, which delineate future vessels. Pillar resha** and fusions determine the new vascular entity. Pillars and folds are then formed in the capillary sheet, which separate the new vessels from the old capillary plexus. Intussusceptive branching remodeling adapts the branching angle and the bores of the branches of new supplying and draining vessels by insertion of transluminal pillars at branching points (abundant small holes are observed at branching sites). The combined cross-sectional area of the branches is greater than that of the stem: R\(_{t}^{p} =\) R\(_{b1}^{p}+\) R\(_{b2}^{p}\) (subscripts t and b for trunk and branch) with 2  < p  < 4, p depending both on the trunk bore and the vessel type (supplying or draining). The area ratio is indeed significantly different in arteries and veins [1176]. The distribution of blood flow at each bifurcation depends on the asymmetry ratio between the two branches. Strong asymmetry can lead to vascular pruning (non-perfusion and removal of branches at bifurcations). The time needed to complete pillar formation ranges from 40 to 120 mn.

  7. 7.

    The exocyst complex is composed of 8 proteins: Sec3, Sec5, Sec6, Sec8, Sec10, and Sec15, as well as Exo70 and Exo84.

  8. 8.

    Protein RabIn8 is homologous to Rab3a-interacting protein (RabIn3), hence its name RabIn3-like protein. Protein RabIn8 stimulates nucleotide exchange on Rab8, but not Rab3a and Rab5, hence being a Rab8-specific activator [1179].

  9. 9.

    Monomeric GTPase CDC42 is recruited to PIP2-rich sites of forming lumens by annexin-2, where it recruits atypical protein kinase-C.Annexin-2 resides transiently in Rab11a + vesicles during lumen formation [1178].

  10. 10.

    In nephrons, apical proteins, such as podocalyxin and Crumbs polarity complexes are delivered to Rab11a + recycling endosomes. Podocalyxin is a sialoglycoprotein of the CD34 family of transmembrane sialomucins. It is a constituent of the glycocalyx of podocytes that acts in podocyte morphogenesis. The apical Crumbs homolog complex keeps the atypical protein kinase-C apical during complex cellular shape changes. The apical-polarity determinant Crumbs complex is essential for lumen formation [1177]. The Crumbs complex associates with the Par complex directly or via the Crb complex protein Membrane protein, palmitoylated MPP5 of the P55-like MAGUK (membrane-associated guanylate kinase) subfamily (a.k.a. protein associated with Lin-7 PALS1). In addition, Crumbs homologs promote the dissociation of Par3 from Par6 and aPKC, hence allowing Par3 to localize to apicolateral borders during the transition from AMISs to preapical patches [1177].

  11. 11.

    Rab8 GTPase modulates polarized membrane transport via reorganization of actin and microtubules. Rab8 GTPase regulates membrane transport associated with TNFα-mediated stress responses and cell morphogenesis [1179].

  12. 12.

    TBC (Tre2 proto-oncogene [ubiquitin-specific peptidase USP6], BUB2 [budding uninhibited by benzimidazoles], and CDC16) motif-containing proteins pertains to GTPase activators of Rab and Rab-like GTPases.

  13. 13.

    The CDC42-specific GEF dynamin-binding protein (DnmBP; a.k.a. Tuba according to the tradition of naming large synaptic proteins after musical instruments) concentrates at the apical region of cell junctions in epithelia via its interaction with zonula occludens protein ZO1. Scaffold Tuba links dynamin, Rho GTPase, and the actin cytoskeleton. It connects dynamin to numerous actin regulators [1180].

  14. 14.

    A.k.a. chicken ovalbumin upstream promoter transcription factor COUPTF2).

  15. 15.

    A.k.a. arresten, canstatin, metastatin, and tumstatin.

  16. 16.

    A.k.a. endorepellin.

  17. 17.

    A.k.a. anastellin.

  18. 18.

    A.k.a. endostatin and neostatin.

  19. 19.

    A.k.a. vastatin.

  20. 20.

    A.k.a. restin.

  21. 21.

    A.k.a. basement-membrane protein BM40 and osteonectin.

  22. 22.

    The Sparc gene is generally detected in cells with high rates of matrix production and proliferation. It can be identified in osteoblasts, odontoblasts, and chondrocytes, as well as megacaryocytes, steroid-producing cells of adrenal glands and gonads, and cells of kidney glomeruli, bronchi, skin, and large vessels [1188].

  23. 23.

    Peptides derived from SPARC domain-4 binds to endothelial cells and impedes endothelial cell proliferation, like SPARC. This inhibition also results from the action of a peptide derived from the follistatin-like domain-2. On the other hand, peptides from SPARC domain-1 and -3 have no effect on VEGF-stimulated DNA synthesis in endothelial cells [1187]. The inhibition of proliferation of human microvascular endothelial cells is caused by, at least partly, VEGF–SPARC binding.

  24. 24.

    Lactadherin is also known as milk fat globule-EGF factor-8 (MFGE8).

  25. 25.

    Transmembrane glutamate carboxypeptidase-2 is also named prostate-specific membrane antigen.

  26. 26.

    Inhibition of P21-activated kinase-1 enhances the association of glutamate carboxypeptidase-2 with filamin-A.

  27. 27.

    The vascular network is locally composed of arteriolar branched and venular junctional networks interconnected by the capillary bed. These arteriolar and venular networks are afferent to and efferent from irrigated tissues, or efferent from and afferent to the heart pump, respectively. As the heart can be defined as the center of circulating blood circuitry, the latter meaning is preferable.

  28. 28.

    The ephrin-B2–EPHb4 signaling is involved in arteriovenous differentiation. Four Slit receptors exist, the Roundabouts (Robo). Receptor Robo4 and plexin-D1 are expressed by endothelium. Semaphorin-3 inhibits endothelial cell motility via plexin-D1. Neuropilins, in competition with Sema3a, associate with VEGF receptors and allow binding of heavy VEGF isoforms to endothelial cell receptors. Netrin-1 acts on both the endothelial cells and smooth myocytes of the vessel wall. It can have repulsive and attractive effects, according to the context. Neogenin is expressed in vascular smooth myocytes, whereas Unc5 is expressed in endothelial cells.

  29. 29.

    Slits are proteic chemorepellants in axon guidance and neuronal migration via the Roundabout receptor. Robo1 is expressed by vascular endothelial cells. Slit2 attracts endothelial cells.

  30. 30.

    Neuropilin-1 and -2 that bind semaphorin-3A (or collapsin-1) are involved in axon guidance. They are also receptors for heparin-binding VEGFa isoforms. Both Sema3a–Nrp1 and VEGF–Nrp1 signaling are required for heart development.

  31. 31.

    Netrin-1 is particularly expressed in the develo** lungs, pancreas, and mammary gland.

  32. 32.

    Presenilin-1 is a widespread transmembrane protein. It is cleaved into N-terminal (NPS1) and C-terminal (CPS1) fragments that associate to form a functional heterodimer. It promotes γ-secretase processing of substrates.

  33. 33.

    C-terminal Src kinase (CSK) binds Src kinase and prevents its activation by precluding its autophosphorylation (Tyr418).

  34. 34.

    A.k.a. translocation ETS leukemia protein (Tel or Tel1) and malignant proliferation, eosinophil (MPE).

  35. 35.

    Plasmin hydrolyzes many extracellular proteins. Urokinase and tissue-type plasminogen activators have high affinity for inactive plasminogen to produce plasmin. Conversely, plasminogen activator inhibitors PAI1 and PAI2 prevent the activation of plasminogen into plasmin.

  36. 36.

    Enzyme HDAC7 is transiently and strongly expressed in CD4 + , CD8 + thymocytes, as it represses a pro-apoptotic gene that encodes nuclear receptor NR4a1 (a.k.a. testicular receptor TR3, nerve growth factor NGF1b, and Nur77). Enzyme HDAC7 in the vascular endothelium downregulates MMP10 matrix metallopeptidase.

  37. 37.

    Two miR23–miR27–miR24 clusters exist: an intergenic miR23a–miR27a–miR24-2 and intronic miR23b–miR27b–miR24-1 cluster.

  38. 38.

    Mathematical reaction–diffusion discretized and continuous models of pattern formation represent either cells as points or as local physicochemical characteristics in a continuum. In the cell form of the model, mechanical aspects are related to cell positions, masses, velocities, and elastic properties, as well as intercellular forces, and chemical aspects to the chemical composition and diffusivity of each separate cell. In the continuous form of the model, mechanical aspects are described by stress, velocity, density, and elasticity of the matter, and chemical aspects by concentration and diffusivity in each point. Chemical reactions include production, conversion, and degradation of morphogens.

  39. 39.

    Delta-like ligand DLL4 is a Notch agonist via Notch-1 and Notch-4 receptors devoted to the specific development of the arterial endothelium.

  40. 40.

    Nuclear receptor NR2f2, or chicken ovalbumin upstream promoter transcription factor COUPTF2, inhibits the activity of many transcription factors, such as intracellular receptors retinoic acid (RAR or NR1b), retinoid X (RXR or NR2b), and thyroid (TR or NR1a) and steroid hormone (SF1 or NR5a1) receptors. Transcription factor NR2f2 is able to bind to DNA either as a homo- or heterodimer. Two NR2f types are encoded by the NR2F1 and NR2F2 genes. Factor NR2f2 is highly expressed in the venous endothelium, but not the arterial one. Transcription factor NR2f2 is also involved in the formation of atrioventricular septum and coronary vessels.

  41. 41.

    The homeobox gene product Prox1 is expressed in certain endothelial cells that yield buds from veins to give rise to lymphatics.

  42. 42.

    Tumor growth rate is not correlated with tumor vascular density. Tumor perfusion could be improved by vasculature pruning. Repression of DLL4 results in excessive angiogenesis. Normally, endothelial cell stimulation by multiple growth factors leads to cell proliferation with controlled degradation of the extracellular matrix and migration using various chemoattractants and adhesion molecules. Endothelial cells then form a central lumen and mature into a functional vessel. Neutralized DLL4 leads to defective cell fate and impairs formation of tubular structures by endothelial cells. Most tumor vessels are not functional; they are either not perfused or convey a reduced blood flow.

  43. 43.

    Protein CCM1 is produced in astrocytes and endothelial cells. It complexes with CCM2 and CCM3, as well as lipids and components of the cytoskeleton, cell junctions, and signal transduction pathways.

  44. 44.

    A.k.a. pre-adipocyte factor-1 (PreF1). It precludes differentiation into adipocytes, neuroendocrine cells, osteoblasts, myocytes, and hematopoietic cells.

  45. 45.

    In vitro, VEGF is implicated in the survival, proliferation, and migration of Schwann cells, astrocytes, and microglia [1258]. In vivo, VEGF is required for migration of certain motoneurons.

  46. 46.

    The PKD family includes PKD1 to PKD3. Kinases PKD1 and PKD3 are also called PKCμ and PKCν, respectively. PKD1 is a class-2a HDAC export kinase.

  47. 47.

    Receptor VEGFR1 is implicated in chemotaxis and vascular permeability.

  48. 48.

    Receptor VEGFR2 is involved via protein kinase-B and mitogen-activated protein kinase in endothelial cell proliferation and survival.

  49. 49.

    Growth factors VEGFb and PlGF are selective ligands of VEGFR1 (Vol. 3 – Chap. 8. Receptor Kinases).

  50. 50.

    A.k.a. calcipressin-2 [(Cps2).

  51. 51.

    Kinase LIMK1 is also phosphorylated by RoCK and PAK, downstream from Rho GTPases.

  52. 52.

    Cofilin phosphatases slingshot and chronophin dephosphorylate (activate) cofilin. Overexpression of LIMK1 suppresses cell motility [1268, 1269].

  53. 53.

    Filamin-A, the most abundant, is widespread, whereas filamin-B, also broadly expressed, is produced mainly in endothelial cells. Filamin-C is primarily expressed in skeletal myocutes.

  54. 54.

    A.k.a. metal-regulatory transcription factor-1 (MTF1).

  55. 55.

    The AP1 family is composed of dimeric protein complexes formed by products of Jun, Fos, and ATF gene families. Hypoxia upregulates AP1 expression that activates target genes for endothelin-1 and PDGFb in endothelial cells.

  56. 56.

    Hypoxia-responsive transcription factor JunB is activated by numerous stimuli, such as NFκ B and inflammatory cytokines. Other AP1 subunits Jun and Fos act as partners of VEGF response to hypoxia.

  57. 57.

    A cis-acting RNA element in the 3′ UTR of the ceruloplasmin mRNA.

  58. 58.

    Interferon-γ activates a kinase cascade.Death-associated protein kinase DAPK1 activates DAPK3 that phosphorylates L13a [1276]. Both Dapk1 and Dapk3 mRNAs contain a 3′UTR GAIT element. They are thus translationally repressed by the GAIT complex. This negativefeedback prevents complete suppression of translation, thereby allowing a low-level translation of target transcripts such as VegfA mRNA.

  59. 59.

    Platelet-derived growth factors form dimers that bind and activate their receptor tyrosine kinases PDGFRα and PDGFRβ that also build dimers. Both PDGFc and PDGFd are produced as latent growth factors that require proteolytic removal of their N-terminal CUB (complement subcomponents C1r and C1s, fibropellin-1, or uEGF, from Strongylocentrotus purpuratus (Purple sea urchin), and bone morphogenetic protein BMP1) domain to become active.

  60. 60.

    Platelet-derived growth factors PDGFaa, PDGFab, PDGFbb, and PDGFcc activate PDGFRαα homodimers, PDGFbb and PDGFdd stimulate PDGFRββ homodimers, and PDGFab, PDGFbb, PDGFcc, and PDGFdd activate PDGFRαβ heterodimers.

  61. 61.

    During tumoral angiogenesis, pericytes have morphological abnormalities.

  62. 62.

    The transient apoptotic effect on endothelial cells of TGFβ1 is followed by refractoriness of these cells to TGFβ1-induced apoptosis.

  63. 63.

    Prolactin operates in reproduction, growth, metabolism, immunity, osmoregulation, and behavior. Growth hormone not only stimulates growth, but also modulates metabolism, reproduction, and immunity, among other activities. Placental lactogen acts on mammary development, corpus luteum maintenance, and progesterone production.

  64. 64.

    The bone morphogenetic protein BMP1 family comprises structurally similar metallopeptidases: BMP1, mammalian Tolloid, and mammalian Tolloid-like Tll1 and Tll2. BMP1-like peptidases participate in the formation of the extracellular matrix by processing precursors: procollagens-1, -3, -5, -7, and -11 into functional ECM components; prolysyl oxidase zymogen into enzyme that catalyzes crosslinks in collagens and elastins; prolaminin-5; precursors of proteoglycans biglycan and osteoglycin; etc. BMP1-like peptidases activate certain TGFβ complexes, including BMP2, BMP4, GDF8, GDF11, and TGFβ1.

  65. 65.

    Interleukin-20 belongs to the IL10 family with IL10, IL19, IL22, IL24, and IL26. Many cell types produce IL20, such as monocytes and epithelial and endothelial cells.

  66. 66.

    The endothelial receptor protein Tyr kinase with Ig and EGF homology TIE2 is also termed Tyr-protein endothelial kinase TEK. Receptor TIE1 may build TIE1–TIE2 heterodimers to contribute to TIE2 signal transduction. Besides, Ang1–TIE2 signaling operates in the maintenance of hematopoietic stem cells.

  67. 67.

    Apelin localizes preferentially in blood vessels. An immature peptide, preproapelin, is secreted and cleaved by proteases to form apelin13, apelin17, and apelin36, among others. These isoforms have different receptor-binding affinities and activities. Apelin has a positive inotropic effect and can cause vasoconstriction and vasodilation (via NO) according to circumstances.

  68. 68.

    Receptor APJ is widespread in embryos and adults, especially in the lung and heart, as well as in vascular and endocardial endothelial and smooth muscle cells.

  69. 69.

    In endothelial cells, PI3Kc1β operates downstream from liganded G-protein-coupled receptors such as CXCR4 α-chemokine receptor. In these cells, PI3Kc1δ is expressed at low concentration. Catalytic subunits of class-1A PI3K isoforms PI3Kc1α and PI3Kc1β are ubiquitous, whereas PI3Kc1δ is only enriched in leukocytes.

  70. 70.

    This transient signaling is associated with normal microvascular development, acute PKB activation of myristoylated PKB (PKBM) being cardioprotective.

  71. 71.

    Thrombospondins are involved not only in endothelial cell proliferation and apoptosis, but also in collagen assembly and maintenance of vascular integrity. Thrombospondin-2 controls the level of matrix metallopeptidase MMP2 [1316].

  72. 72.

    Substrates of ADAMTS1 also include aggrecan, versican, and nidogen. It is associated with catalytic modifiers such as fibulin-1. Moreover, ADAMTS1 has a non-catalytic function, as it sequesters VEGF factor.

  73. 73.

    Girdin is also known as Akt (PKB) phosphorylation enhancer (APE), Gα-interacting vesicle-associated protein (GIV), and Hook-related protein-1 (HkRP1). Kinase PKB phosphorylates girdin to regulate its subcellular location and fibroblast migration.

  74. 74.

    After blood vessel injury, tissue factor with factor VIIa activates factor Xa, thrombin, and fibrin to build a hemostatic plug.

  75. 75.

    Hydrogen sulfide activates ERK1 and ERK2 in monocytes, smooth myocytes, and gastric epithelial cells [1327]. It stimulates P38MAPK in smooth muscle and β cells, but precludes P38MAPK phosphorylation in neutrophils and microglial cells.

  76. 76.

    Inhibition of endothelial NO synthase (NOS3) or PKG1 abolishes H2S-triggered angiogenesis and attenuates H2S-primed vasorelaxation. Conversely, inactivation of H2S synthase cystathionine γ-lyase supresses NO-stimulated cGMP accumulation and angiogenesis and reduces acetylcholine-stimulated vasorelaxation [1328].

  77. 77.

    These adducts localize to oxidized low-density lipoprotein and accumulate in atherosclerotic plaques as well as retina, where they promote choroidal neovascularization and age-related macular degeneration. These adducts, carboxyethylpyrrole (CEP) in particular, are transiently observed during wound healing. At injury sites, they reach a maximum concentration 3 days after damage and return to original levels when the healing is completed. High levels of CEP correlate with intense vascularization of damaged tissue.

  78. 78.

    Factor VEGF during the early stage of angiogenesis activates cell migration and sprouting. Angiopoietin-1 mediates the interactions between endothelial and smooth muscle cells. Angiopoietin-2 disrupts these interactions to promote independent migration. Both Ang1 and Ang2 are produced by vascular cells, bind to receptor TIE2, and act synergistically with VEGF to regulate angiogenesis. Homodimer PDGFbb released by endothelial cells at a late stage of angiogenesis recruits smooth muscle cells to stabilize the nascent sprouts.

  79. 79.

    NADPH oxidase also localizes to the endoplasmic reticulum. Mitochondria are another major ROS sources.

  80. 80.

    Soluble VEGFR1S also binds VEGFb and placenta growth factor. Agent VEGFR1S forms heterodimers with VEGFR2 receptor. Avascularity may be maintained by multiple redundant mechanisms associated with many anti-angiogenic molecules that exist in the cornea, but neutralization of VEGFR1S alone abolishes corneal avascularity. VEGFR1S also regulates the availability of VEGFa in cyclic vascularization and embryonic sprouting.

  81. 81.

    Thrombospondins constitute 2 subsets: subset A with Tsp1 and Tsp2 homotrimers and subset B with Tsp3 to Tsp5 homopentamers.

  82. 82.

    Regulator of G-protein signaling RGS5 is a marker for pericyte progenitor cells.

  83. 83.

    Activation of matrix metallopeptidase-9 leads to the release of soluble SCF, which promotes the proliferation and motility of circulating endothelial precursors.

  84. 84.

    Molecule CA4P binds to tubulin. It selectively targets endothelial cells, but not smooth myocytes.

  85. 85.

    A.k.a. RING finger protein RNF71 and tripartite motif-containing protein TRIM19.

  86. 86.

    Promyelocytic leukemia, which regulates tumor suppressor transcription factors, is lost in various types of human cancers.

  87. 87.

    Many pericytes survive after VEGF inhibitor administration. However, the pericyte phenotype reversibly changes during treatment, with a downregulation of the expression of α-smooth muscle actin. This change reverses when the treatment is stopped.

  88. 88.

    Manganese-containing enzyme SOD2 (MnSOD) resides in the mitochondrial matrix. Secreted, copper-containing SOD3 (CuSOD) lodges in the extracellular matrix.

  89. 89.

    A.k.a. liver receptor homolog-1.

  90. 90.

    Nineteen ETS transcription factors are expressed in blood vessel endothelial cells.

  91. 91.

    Receptor VEGFR3 exists in all vascular endothelia during embryo- and fetogenesis, whereas in adults, it is restricted to the lymphatic endothelium. However, VEGFR3 is observed in the microvasculature of tumors and wound healing. In adult humans, VEGFR3 is also synthesized in some fenestrated and discontinuous endothelia of blood vessels. Receptor VEGFR3 promotes the migration and proliferation of lymphatic endothelial cells.

  92. 92.

    Neuropilin-2 is a semaphorin receptor of the nervous system and lymphatic capillaries. Combined inhibition of VEGFR2 and VEGFR3 prevents angiogenesis and tumor growth [1366].

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Thiriet, M. (2013). Vasculature Growth. In: Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems. Biomathematical and Biomechanical Modeling of the Circulatory and Ventilatory Systems, vol 5. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5966-8_10

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