Vascular Endothelial Growth Factor
One of the earliest responses to hypoxia/MV repair is the expression of vascular endothelial growth factor, the tie-1 and tie-2 receptors, and angiopoietin (Ang), which are all obligatory for angiogenesis. The VEGF family comprises at least five isoproteins, whose effects are mediated by three VEGF receptors (VGR), which in turn communicate with ECs via RTKs. Regulation of the VEGF gene is controlled by the stabilization of hypoxia. VEGF mRNA levels dramatically increase when endothelial cell cultures are exposed to hypoxia and return to normal when oxygen supply is restored. VEGF isoforms vary in their actions. For example, VEGF121 and VEGF165 and their receptors increase and VEGF189 decreases MV lumen size.
Other peptide growth factors that promote MV repair are basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), transforming growth factor b (TGFb), and insulin-like growth factor (IGF-1). However, unlike VEGF, these peptides tend not to be specific for ECs and also promote the proliferation of fibroblasts, VSMCs, and other cells. One facet of the angiogenic process is that MMPs liberate these growth factors from tight association with the matrix. Apart from augmenting angiogenesis directly, bFGF augments the accumulation of inflammatory cells and PDGF recruits pericytes and VSMCs around nascent vessel sprouts.
Angiopoietins are axiomatic in mediating angiogenesis and interact at many levels with VEGF. Angiopoietin 1 (Ang 1), a ligand for the endothelial receptor, Tie2, inhibits permeability, and overexpressing Angl promotes an increase in lumen diameter. Ang 1 via phosphorylation of Tie 2 is chemotactic for ECs and induces sprouting and stimulates EC-pericyte interactions. Angiopoietin 2 (Ang 2) is a natural antagonist of Angl and is involved in detaching VSMCs and loosening underlying matrix, thereby allowing ECs to migrate. Ang 2 in concert with VEGF promotes angiogene-sis, but alone it can be an inhibitor.
Endothelin, Nitric Oxide, Prostacyclin, and Other Endothelial Factors
Perhaps not surprisingly, angiogenesis is controlled and modulated by those factors manufactured by ECs. These include nitric oxide (NO), endothelin-1 (ET-1), tissue plasminogen activator (tPA), thrombospondin, von Willebrand factor, and prostaglandins.
NO plays an axiomatic role in mediating angiogenesis. VEGF augments NO release from ECs and NO mediates VEGF-stimulated EC proliferation. VEGF-stimulated NO release from simian virus-40 immortalized microvascular ECs and induced cell migration, whereas the nitric oxide synthase (NOS) inhibitor L-NAME or antisense oligonucleotides to endothelial NOS (eNOS) suppressed this effect. In an in vivo model of angiogenesis in the rabbit cornea, NO potentiated the proangiogenic effect of substance P that was prevented by the absence of L-arginine, the substrate for NO formation.
ET-1 is a potent mitogen for both ECs and VSMCs but appears to act more as a promoter of other angiogenic factors, rather than being a primary stimulator. For example, when combined with VEGF, ET-1 induces angiogenesis in subcutaneously implanted matrigel plugs in mice. ET-1 may induce angiogenesis via the upregulation of VEGF and/or iNOS. There are conflicting reports as to which receptor subtype mediates angiogenesis, with both ETA and ETB receptors having been implicated. There may also be considerable species-dependent variations and differences between different vascular beds.
Prostaglandins, Thromboxanes, and Leukotrienes (Eicosanoids)
Thromboxane A2, a major release factor of platelets, appears to be the most potent in promoting angiogenesis. In a corneal model, activated human microvascular cells generate TXA2, and selective cyclooxygenase-2 (COX-2) antagonists inhibited TXA2 production along with endothelial cell migration and corneal angiogenesis. bFGF and VEGF increase TXA2 synthesis. The TXA2-mimetic U46619 stimulates endothelial cell migration, whereas a TXA2 antagonist (SQ29548) inhibited bFGF- and VEGF-stimulated endothelial cell migration.
With regard to the prostaglandins (PGs), which are produced principally by blood vessels, PGE1 and PGE2 promote angiogenesis in a rat femoral artery model. PGE2 induces expression of VEGF in fibroblasts. Indomethacin (a nonselective cyclooxygenase inhibitor) reduces EC migration.
Lipoxygenase derived 12-5"-hydroxyeicosatetraenoic acid (12-S-HETE) and cytochrome P450 derived 12-R-HETE (derived principally from leukocytes) are pro-angio-genic factors. The angiogenic potency of 12-R-HETE is equal to that of bFGF. VEGF-induced endothelial cell migration can be partially reversed by adding 12-S-HETE. Leukotrienes (LTs), in particular LTC4, stimulate endothelial cell migration and tube formation. In an in vivo chick chorioallantoic membrane system LTC4 and LTD4 promoted angiogenesis in a dose-dependent manner that was abolished by selective LT antagonists.
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