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PubMed1997

Regulation of capillary formation by laminin and other components of the extracellular matrix.

The process of angiogenesis (vessel formation) and the resulting stabilization of the mature vessel are complex events that are highly regulated and require signals from both serum and the extracellular matrix. Endothelial cells rest on a specialized thin extracellular matrix known as the basement membrane. Endothelial cells lining normal blood vessels are usually quiescent. When a proper stimulus is present, angiogenesis beings when endothelial cells degrade their basement membrane and invade the surrounding extravascular matrix. Formation of new vessels involves the migration and proliferation of cells. To assist the cells in their migration, the extravascular matrix provides an environment rich in stromal collagen fibers, fibrin, hyaluoronic acid, vitronectin and fibronectin. Once the endothelial cells assemble to form a new vessel, the cells secrete a basement membrane that helps to stabilize and maintain the vessel wall. The basement membrane adheres tightly to cells comprising the vessel wall, provides inductive signals, and plays a important role in the homeostasis of new vessels. We have demonstrated that two major components of the basement membrane, laminin and collagen IV, possess endothelial cell binding sites which regulate vessel stability. In this chapter, we will define the role of these molecules in endothelial cell behavior.

Amino Acid Sequence↗
PubMed1997

Regulation of angiogenesis by scatter factor.

Scatter factor (SF, hepatocyte growth factor) is a cytokine that stimulates motility, proliferation, and morphogenesis of epithelia. These responses are transduced through a tyrosine kinase receptor that is encoded by a proto-oncogene (c-met). SF is a potent angiogenic molecule, and its angiogenic activity is mediated, in part, through direct actions on endothelial cells. These include stimulation of cell motility, proliferation, protease production, invasion, and organization into capillary-like tubes. SF also stimulates the proliferation of smooth muscle cells and pericytes, cell types that also participate in the formation of capillaries and other microvessels. SF is chronically overexpressed in tumors, and it is postulated SF may function as a tumor angiogenesis factor. SF production in tumors may be due, in part, to an abnormal tumor: stroma interaction in which tumor cells secrete soluble proteins (SF-inducing factors) that stimulate stromal cell SF production and in part to autocrine production by the tumor cells themselves. Recent studies suggest a linkage between tumor suppressors (anti-oncogenes) and inhibition of angiogenesis. We hypothesize that tumor suppressor gene mutations may contribute to activation of an SF-->c-met signalling pathway, leading to an invasive and angiogenic tumor phenotype. Modulation of this pathway may provide clinically useful methods of enhancing or inhibiting angiogenesis.

Adult↗
PubMed1999

Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis.

This Chapter has reviewed the literature concerning VPF/VEGF as a potent vascular permeabilizing cytokine. In accord with this important role, microvessels have been found to be hyperpermeable to plasma proteins and other circulating macromolecules at sites where VPF/VEGF and its receptors are overexpressed, i.e., in tumors, healing wounds, retinopathies, many important inflammatory conditions and in certain physiological processes, such as ovulation and corpus luteum formation. Moreover, microvascular hyperpermeability to plasma proteins was shown to have an important consequence: the laying down of a fibrin-rich extracellular matrix. This provisional matrix, in turn, favors and supports the ingrowth of fibroblasts and endothelial cells which, together, transform the provisional matrix into the mature stroma characteristic of tumors and healed wounds. Finally, we have considered the pathways by which these and other circulating macromolecules cross the endothelium of normal and VPF/VEGF-permeabilized microvessels. These pathways include VVOs and trans-endothelial openings that have been variously interpreted as inter-endothelial cell gaps or trans-endothelial cell pores. At least some trans-endothelial cell pores may arise from VVOs. In conclusion, these data provide new insights into the mechanisms of angiogenesis and stroma formation, insights which are potentially applicable to a wide variety of disease states and which may lead to identification of new targets for therapeutic intervention.

Animals↗
PubMed1995

Angiogenesis: mechanistic insights, neovascular diseases, and therapeutic prospects.

This review of angiogenesis aims to describe (a) stimuli that either elicit or antagonize angiogenesis, (b) the response of the vasculature to angiogenic or anti-angiogenic stimuli, i.e., processes required for the formation of new vessels, (c) aspects of angiogenesis relating to tissue remodeling and disease, and (d) the potential of angiogenic or antiangiogenic therapeutic measures. Angiogenesis, the formation of new vessels from existing microvessels, is important in embryogenesis, wound healing, diabetic retinopathy, tumor growth, and other diseases. Hypoxia and other as yet ill-defined stimuli drive tumor, inflammatory, and connective tissue cells to generate angiogenic molecules such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-beta (TGF-beta), platelet-derived growth factor (PDGF), and others. Natural and synthetic angiogenesis inhibitors such as angiostatin and thalidomide can repress angiogenesis. Angiogenic and antiangiogenic molecules control the formation of new vessels via different mechanisms. VEGF and FGF elicit their effects mainly via direct action on relevant endothelial cells. TGF-beta and PDGF can attract inflammatory or connective tissue cells which in turn control angiogenesis. Additionally, PDGF may act differently on specific phenotypes of endothelial cells that are engaged in angiogenesis or that are of microvascular origin. Thus phenotypic traits of endothelial cells committed to angiogenesis may determine their cellular responses to given stimuli. Processes necessary for new vessel formation and regulated by angiogenic/antiangiogenic molecules include the migration and proliferation of endothelial cells from the microvasculature, the controlled expression of proteolytic enzymes, the breakdown and reassembly of extracellular matrix, and the morphogenic process of endothelial tube formation. In animal models some angiogenesis-dependent diseases can be controlled via induction or inhibition of new vessel formation. Life-threatening infantile hemangiomas are a first established indication for antiangiogenic therapy in humans. Treatment of other diseases by modulation of angiogenesis are currently tested in clinical trials. Thus the manipulation of new vessel formation in angiogenesis-dependent conditions such as wound healing, inflammatory diseases, ischemic heart and peripheral vascular disease, myocardial infarction, diabetic retinopathy, and cancer is likely to create new therapeutic options.

Animals↗