Regulation Microvascular: Smooth Muscle Contraction ECM-Integrin-Cytoskeletal

微血管平滑肌细胞（mVSMC）需要与其环境的物理连接， 调节血管直径。这对于控制组织血流和动脉压至关重要。粘附 整合素和细胞外基质（ECM）蛋白之间的相互作用提供了与细胞外基质（ECM）蛋白之间的必要联系。 用于双向传递机械力和细胞信号的细胞骨架。我们有令人信服 ASBI和AVBA是控制血管张力和血管肌原性的重要整合素的证据 反应我们还观察到asbi与纤维连接蛋白（FN）、胶原Ⅰ（COL-1）和玻连蛋白（Vitronectin）的粘附， (VN)与FN和COL-I相关的最强结合和信号传导显著不同。项目1将 重点关注asbi和aibs整合素与FN、COL-1和VN的粘附如何受到血管收缩剂的影响， 血管扩张剂我们的研究集中在这样的前提下，即整合素与ECM的粘附被任何细胞因子改变。 影响血管张力的因素。项目1的中心假设是整合素粘附是 在收缩激活期间，mVSMC动态上调， 以支持血管直径的变化。将在单个mVSMC中检验该假设 使用原子力显微镜定量整联蛋白粘附和细胞活化/细胞骨架刚度， 孤立小动脉的直径记录。腺病毒和转染方法模型将用于 观察和操纵选定蛋白质的表达。具体目标是：目标A：确定 血管收缩剂（去甲肾上腺素，血管紧张素11，KCl）和血管扩张剂（NO，腺苷）对asbi或 在mVSMC中avba整合素与FN、CN-1和VN粘附。目的B：确定如何选择局部粘连 蛋白质（asbi和ajoz整联蛋白、α-辅肌动蛋白、黏着斑蛋白、talin-1和桩蛋白）和细胞骨架（肌动蛋白和 微管）参与血管收缩剂和血管扩张剂诱导的粘附变化。AIM C 确定小动脉的反应性和离体小动脉对血管收缩剂的Ca^* 信号是如何被改变的， ASBI或AVBS整联蛋白的抑制。这些研究意义重大，将增进我们对 整联蛋白粘附与微血管控制有关。这些研究意义重大，因为它们将提高我们的 了解整合素粘附如何与微血管控制相关。这些信息将提供新的 直接适用于血管疾病中血管功能紊乱的原因的机械见解。 同样的洞察力将被利用来创造新的治疗策略来操纵血管紧张素

Microvascular smooth muscle cells (mVSMC) require physical connections with their environment to regulate vascular diameter. This is essential for control of tissue blood flow and arterial pressure. Adhesion between integrins and extracellular matrix (ECM) proteins provides the necessary connections with the cytoskeleton for bi-directionally transmitting mechanical forces and cellular signaling. We have compelling evidence that asbi and avba are important integrins that control vascular tone and the vascular myogenic response. We have also observed that adhesion of asbi to fibronectin (FN), collagen I (COL-l) and vitronectin (VN), differ significantly with the strongest binding and signaling associated with FN and COL-I. Project 1 will focus on how asbi and a^bs integrin adhesion to FN, COL-l and VN are affected by vasoconstrictors and vasodilators. Our studies are concentrated on the premise that integrin adhesion to ECM is altered by any factors that affect vascular tone. The CENTRAL HYPOTHESIS of project 1 is that integrin adhesion is dynamically up regulated in mVSMC during contractile activation and likewise adaptively down regulated during relaxation to support changes in vessel diameter. This hypothesis will be tested in single mVSMC using atomic force microscopy to quantify integrin adhesion and cell actlvation/cytoskeletal stiffness and with diameter recordings of isolated arterioles. Adenoviral and transfection methods models will be used to observe and manipulate the expression of selected proteins. The specific aims are: AIM A: Determine the effects of vasoconstrictors (norepinephrine, angiotensin 11, KCI) and vasodilators (NO, adenosine) on asbi or avba integrin adhesion to FN, CN-1 and VN in mVSMC. AIM B: Determine how selected focal adhesion proteins (asbi and ajoz integrins, a-actinin, vinculin, talin-1 and paxillin) and the cytoskeleton (actin and microtubules) are involved in vasoconstrictor and vasodilator induced changes in adhesion. AIM C Determine how arteriolar reactivity and Ca^* signaling of isolated arterioles to vasoconstrictors are altered by inhibition of asbi or avbs integrins. These studies are significant and will enhance our understanding of how integrin adhesion is linked to microvascular control. These studies are significant as they will enhance our understanding of how integrin adhesion is linked to microvascular control. This information will provide new mechanistic insight directly applicable to the causes of disturbed vasomotor function in vascular disease. This same insight will be exploitable to create new therapeutic strategies to manipulate vasomotor tone