Regulation Microvascular: Smooth Muscle Contraction ECM-Integrin-Cytoskeletal

调节微血管：平滑肌收缩 ECM-整合素-细胞骨架

• 批准号: 7918613
• 负责人: GERALD A. MEININGER
• 金额: $ 46.4万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-22 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7918613
• 关键词: Actinin; Actins; Adenosine; Adhesions; Affect; Agonist; Angiotensin II; Angiotensins; Arteries; Atomic Force Microscopy; Binding; Biochemical; Blood Pressure; Blood Vessels; Blood flow; Caliber; Cell Adhesion; Cells; Characteristics; Collagen; Cytoskeleton; Data; Development; Dilator; Environment; Event; Extracellular Matrix; Extracellular Matrix Proteins; Felis catus; Fibronectins; Fluorescence; Fluorescence Microscopy; Focal Adhesions; Generations; Goals; Homeostasis; Integrins; Investigation; Knowledge; Laboratories; Laminin; Link; Mechanics; Methods; Microtubules; Modeling; Muscle Contraction; Norepinephrine; PTK2 gene; Play; Process; Proteins; Regulation; Relaxation; Resistance; Role; Series; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Smooth Muscle; Smooth Muscle Myocytes; Stretching; Talin; Technology; Testing; Tissues; Transfection; Transgenic Mice; Vascular Diseases; Vasoconstrictor Agents; Vasodilator Agents; Vasomotor; Vinculin; Vitronectin; Work; adhesion receptor; arteriole; base; design; improved; insight; mouse model; novel; novel therapeutics; paxillin; pressure; research study; response; transmission process; vasoconstriction

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

微血管平滑肌细胞（mVSMC）需要与周围环境建立物理联系