The metabolism of the basement membrane of skin microvessels plays a pivotal role in the regulation of homeostasis, neovascularization, and inflammation. The factors that control these reactions in microvascular endothelial cells are not yet known, but in endothelial cells isolated from patients with recessive dystrophic epidermolysis bullosa, an increase in the rate of conversion of endothelial cells from a classical epithelioid configuration to a spindle-shaped morphology occurs. An explanation for this change in EB cell physiology is not yet known, but it suggests an altered synthesis of a basement membrane components required for the maintenance of vessel homeostasis. In this proposal we will use our basic knowledge of the growth of normal skin microvascular endothelial cells to: 1. Develop a library of cloned skin microvascular endothelial cells from patients with recessive dystrophic epidermolysis bullosa. 2. Determine if the synthesis and degradation of type IV collagen, laminin, and heparan sulfate proteoglycan in cloned EB cells differs from normal skin microvascular endothelial cells. 3. Determine if the inflammatory lymphokines IL-I and TNF-alpha increase the rate of basement membrane degradation and spindle-cell formation. 4. Determine if neovascularization in control and EB cells can be modulated by inhibitors of type IV collagen and heparan sulfate proteoglycans. These studies will provide basic information on the biochemistry of the basement membrane synthesized by normal and EB microvascular endothelial ells and the factors that control its synthesis and degradation.
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