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The investigators will test four hypotheses regarding positive and negative growth control and cytokine- inducible functions of vascular smooth muscle cells (SMC) and endothelial cells (EC): 1. Heparin binding growth factors (HBGFs) contribute to SMC growth during atherogenesis. a) They will monitor expression of FGF family members and heparin binding epidermal growth factor like molecule (HB-EGF) in normal and atheromatous arteries from humans and rabbits. b) They will test whether cytokines regulate HBGF expression by cells found in human atheroma. c) They will study whether membrane bound forms of HB-EGF participate in "juxtacrine" signaling (stimulation requiring cell-cell contact), and whether proteolysis regulates HB-EGF action by release of surface-bound precursors. 2. Certain inflammatory stimuli can mobilize active IL-1beta from a preformed precursor pool in vascular EC. EC in vitro and in vivo contain immunoreactive IL-1beta. They hypothesize that this is inactive 33 kD pro-IL-1beta that requires proteolytic processing for biological activity. They will study the control by inflammatory mediators of IL-1beta processing in EC and SMC which may represent an additional level of local regulation of this multipotent cytokine. 3. Monocyte- colony stimulating factor (M-CSF) promotes SMC growth during atherogenesis. a) They will determine whether human SMC transfected with c-fms, the M-CSF receptor, respond mitogenically to M-CSF. b) They will test whether SMC express membrane bound forms of M-CSF that may participate in "juxtacrine" signaling. c) They will localize c-fms expression in experimental and human atheroma to determine if SMC express this receptor in vivo during atherogenesis. 4. They will test whether local activity of a cytokine inducible nitric oxide synthase (iNOS) in SMC modulates the growth and other non-contractile functions of SMC and other cells. a) They will characterize cDNAs encoding iNOS in SMC. b) They will raise antibodies against SMC iNOS and probe its expression in vivo. c) They will test whether NO or NOS activity modulates the proliferative and matrix stimulatory effects of mediators such as PDGF, TGFs, and HBGFs on SMC. d) They will test whether NO or NOS expression by SMC inhibit mitogenic responses of T-lymphocytes, and might thus modulate local immune responses during vascular diseases.

The results of this study should help unravel mechanisms of arterial pathology, to understand normal vascular homeostasis, and to aid the rational design of therapies for prevalent vascular diseases.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.