Thrombospondin-1 Regulates Vascular Tone

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DESCRIPTION (provided by applicant): Blood vessels, as conduits for blood flow, control blood supply to a particular tissue area through alterations in their size. Such changes in vessel size are regulated by vascular smooth muscle cells (VSMC) which form a part of the wall of most blood vessels. Alterations in the contractility of VSMC directly change the size of blood vessels and can increase or decrease blood flow to tissues. Nitric oxide (NO) is a bioactive gas with wide ranging effects in the body. NO has been identified as a locally important regulator of VSMC contractility. These effects require stimulation of soluble guanylyl cyclase (sGC) by NO and result in rapid relaxation of VSMC. Thrombospondin-1 (TSP1) is a major regulator of vascular cell responses first identified as a secretory product from stimulated platelets. TSP1 is an important inhibitor of angiogenesis. We recently reported that TSP1 can block NO-driven effects in VSMC by blocking stimulation of sGC. Low levels of NO induce vascular cells to become hypersensitive to TSP1, with picomolar concentrations being sufficient to inhibit NO-stimulated VSMC cell responses. Based on our preliminary data we hypothesize that TSP1 regulates tissue blood flow and perfusion through control of NO-activated vascular smooth muscle cell contractility. In support of this hypothesis we propose three specific aims: 1) Demonstrate the effect TSP1 has upon contractile proteins in vascular smooth muscle cells. 2) Demonstrate the effects TSP1 has upon NO-driven vasorelaxation of VSMC. 3) Determine the effects of TSP1 on soft tissue perfusion and oxygen under ischemic stress. These studies should provide increased understanding of the role TSP1 plays in regulating vascular responses to nitric oxide and provide direction in developing therapeutic agents tailored to selectively regulate tissue perfusion.