Hypoxia Inducible Factor and Angiogenesis

It is now clear that vascular architecture in tissues is largely controlled by angiogenic signals from the constituent cells. Local oxygen tension appears to be a critical signal in detecting and responding to local vascular insufficiency; for example, in the retina local ischemia almost always precedes new vessel growth.

HIF and pVHL play a critical role in these responses and many points of interaction with molecular processes

Figure 2 The mechanism of angiogenesis in VHL disease. pVHL is required for the normoxic degradation of HIF-a subunits. In the pVHL-deficient tumor cells, HIF accumulates and effects transcription of its target genes. These include secreted factors such as VEGF, Flt-1, angiopoietins-2, Tie-2, FGF, PDGF, and MCP-1, which act on different stages of angio-genesis, leading to localized new vessel growth. (see color insert)

Figure 2 The mechanism of angiogenesis in VHL disease. pVHL is required for the normoxic degradation of HIF-a subunits. In the pVHL-deficient tumor cells, HIF accumulates and effects transcription of its target genes. These include secreted factors such as VEGF, Flt-1, angiopoietins-2, Tie-2, FGF, PDGF, and MCP-1, which act on different stages of angio-genesis, leading to localized new vessel growth. (see color insert)

regulating angiogenesis have been defined (see Figure 2). The vasculature is usually quiescent in the adult, and endothelial cells are among the longest lived outside the nervous system. High levels of VEGF alone are capable of initiating angiogenesis in these quiescent vessels, and several isoforms of VEGF and its receptors are hypoxia inducible via HIF-dependent processes. In the earliest stages of angiogenesis, vasodilatation and increased vascular permeability, potentially mediated through HIF-regulated genes such as VEGF-A, Flt-1 and nitric oxide synthase, allow extravasation of plasma proteins, which lay down a provisional matrix on which activated endothelial cells migrate. This is accompanied by a loosening of the surrounding pericyte cells that is thought to be mediated by angiopoietin-2 and its tyrosine kinase receptor, Tie-2, both of which again demonstrate induction by hypoxia. The vascular basement membrane and extracellular matrix are then degraded under the balanced control of matrix metallopro-teinases, and the HIF-regulated tissue inhibitor of metallo-proteinase (TIMP-1). Endothelial cells proliferate and migrate into the perivascular space under the control of VEGF, angiopoietins, fibroblast growth factor (FGF), monocyte chemoattractant protein (MCP-1), and platelet-derived growth factor (PDGF), all of which are hypoxically regulated. The endothelial cells then change shape, adhere to one another, and form a lumen. Continued proliferation within the vascular wall allows for enlargement of the vessel lumen. Perivascular cells are recruited and a basal lamina is formed around the new vessel, and finally the vascular sprouts fuse to form loops that circulate the blood.

The involvement of hypoxia and in particular the HIF system at so many points in this complex process suggests that HIF directs a coordinated transcriptional response that is itself sufficient to activate productive angiogenesis. The tight association between VHL mutations that dysregulate HIF and susceptibility to retina and CNS angiomata (see later discussion) strongly suggests that dysregulated HIF activity is directly responsible for this manifestation of the disease. The central role of HIF in the regulation of angio-genesis is also supported by genetic manipulation of the system in rodents. The abnormal vascular development and embryonic lethality seen in the HIF-1a-/- knockout mouse clearly demonstrates the importance of HIF-1a to developmental angiogenesis. Further evidence of the importance of HIF to angiogenesis has come from transgenic expression of constitutively stable HIF-1a mutants or chimeric genes, which result in increased vascularity without the permeability and edema associated with VEGF overexpression alone.

Essentials of Human Physiology

Essentials of Human Physiology

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.

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