The overall goal of this work is to study the effects of circulating hormones on microvascular endothelial cell (MVEC) functions important for wound healing. Compromised microvascular cell physiology is associated with impaired wound healing in diabetic patients and proinflammatory events that cause injury to normal tissues in chronic inflammatory diseases. A number of observations support the concept that insulin, insulin like growth factor I (IGF-I), and adrenal corticosteroids can modulate the responses of MVEC to various procoagulation and proinflammatory factors. The model system to be utilized for these studies is cultured MVEC isolated from bovine precordial adipose tissue. Early events in vascular injury and repair involve an interaction between leukocytes and endothelial cells that may be controlled by endothelial cell production of factors distinct from prostaglandins. The proposed research will assess inflammatory mediators for their ability to stimulate MVEC production of platelet-activating factor (PAF), a lipid autocoid that stimulates the interaction of platelets and leukocytes with vascular endothelial cells. MVEC will also be stimulated by growth factors and inflammatory stimuli to assess their ability to synthesize proteins that are important in the wound repair process such as collagens and collagenases.
The specific aims are to investigate the hypothesis that some circulating hormones (insulin, IGF-I, and adrenal corticosteroids) can modulate MVEC responses to locally released inflammatory mediators and growth factors. Initial studies will investigate the responsiveness of MVEC to insulin and IGF-I by measuring cell proliferation and glucose metabolism. Subsequent studies will assess the effects of inflammatory mediators on MVEC production of PAF and the ability of insulin, IGF-I, and hydrocortisone to modulate PAF production. The third aspect of the proposal is to elucidate the effects of adrenal corticosteroids (hydrocortisone and tetrahydrocortisone) with angiostatic activity on MVEC degradation of basement membrane collagen. The proposed research will provide new information on the physiological role of circulating hormones to alter MVEC functions that are vital to understand angiogenesis, immune reactions and inflammatory responses. The results will expand our insight into disorders such as chronic inflammatory diseases and peripheral vascular problems associated with diabetes.
