Thrombospondin-1 Regulates Vascular Tone

描述（由申请人提供）：血管，作为血液流动的管道，通过改变其大小来控制特定组织区域的血液供应。这种血管大小的变化是由血管平滑肌细胞（VSMC）调节的，它构成了大多数血管壁的一部分。VSMC收缩性的改变直接改变血管的大小，并能增加或减少组织的血流量。一氧化氮（NO）是一种在体内具有广泛作用的生物活性气体。NO已被确定为VSMC收缩性的重要调节因子。这些作用需要一氧化氮刺激可溶性胍基环化酶（sGC），并导致VSMC的快速松弛。血小板反应蛋白-1 （TSP1）是血管细胞反应的主要调节因子，最初被确定为受刺激血小板的分泌产物。TSP1是一种重要的血管生成抑制剂。我们最近报道了TSP1可以通过阻断sGC刺激来阻断no驱动的VSMC效应。低水平的NO诱导血管细胞对TSP1产生超敏反应，而微摩尔浓度足以抑制NO刺激的VSMC细胞反应。根据我们的初步数据，我们假设TSP1通过控制no激活的血管平滑肌细胞收缩性来调节组织血流量和灌注。为了支持这一假设，我们提出了三个具体目标：1)证明TSP1对血管平滑肌细胞中收缩蛋白的影响。2)验证TSP1对no驱动的VSMC血管松弛的影响。3)测定缺血应激下TSP1对软组织灌注和氧的影响。这些研究将有助于进一步了解TSP1在调节血管对一氧化氮的反应中所起的作用，并为开发适合于选择性调节组织灌注的治疗剂提供方向。

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.