The primary triggers for MV repair associated with wounds and trauma are those derived from blood cells and thrombi. Immediately after severance of microvessels, platelets, neutrophils, monocytes, and T cells accumulate at the sites of injury. Platelets are programmed to recognize vascular severance and rapidly change shape and adhere to block the breach in the vessel wall by forming a platelet plug. They simultaneously release a battery of prothrom-botic factors to promote thrombus formation to consolidate the plug, as well as releasing vasoconstrictors (thromboxane A2 and serotonin) that further restrict blood loss. Components of thrombogenesis, such as fibrin, fibrinogen, tissue factor, and factor Xa, are among the most potent angiogenic factors known. Other platelet release substances are also proangiogenic.
Once blood loss has been checked, neutrophils and monocytes rapidly accumulate in a second wave that has a twofold purpose: (1) to destroy bacteria and prevent wound infection and (2) to engender tissue repair including the reestablishment of the local MVs. Thus, neutrophils and monocytes release yet another battery of factors that promote angiogenesis. Monocytes then become resident macrophages, which again release factors that modulate tissue repair and angiogenesis. Indeed, macrophages are deemed the principal orchestrators of inflammatory angiogenesis. Giant cells, which are amalgamations of many macrophages, are coincidentally associated with microves-sel proliferation in arteritis.
Hypoxia is a major initiating factor for and indeed the raison d'être for angiogenesis. Stimulated by the barrage of triggers mentioned earlier, as well as hypoxia, ECs are activated and respond by immediately expressing genes that will result in EC proliferation, migration, and angiogenesis, principal among which are the hypoxia inducible factors (HIFs), peptide growth factors, activator protein-1 (AP-1), early growth response 1 (EGR-1), nuclear factor inter-leukin-6 (NF-IL6), and nuclear factor kappa B (NFkB). HIF is an ab heterodimer. HIF-1a and HIF-1P are constitutively expressed, whereas HIF-1a subunits are inducible by hypoxia. HIF-1 binds to a consensus region of the gene termed the hypoxia response element (HRE). HIF-1a is subjected to rapid ubiquination and proteasomal degradation, a process that is inhibited under normoxic conditions. Apart from hypoxia, cytokines, peptide growth factors, insulin and basic fibroblast growth factor (bFGF) all upregulate hypoxic inhibitory factor 1a (HIF1a) protein expression as well as HIF-1 DNA binding activity and HIF-1 target gene expression. Phosphorylation plays an important role in mediating HIF activity. Intracellular signal transduction systems include Ras/Raf/MAP kinase and receptor tyrosine kinase, PI3 kinase, and PTEN Akt kinase pathways. There are a large number of target genes for HIF-1, which include VEGF, VEGF receptor FLT-1, PAI1, inducible nitric oxide synthase (iNOS), and ceruloplasmin.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.