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 a5b1 and avb3 are important integrins that control vascular tone and the vascular myogenic response. We have also observed that adhesion of a5b1 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 a5b1 and avb3 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 activation/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 a5b1 or avb3 integrin adhesion to FN, CN-1 and VN in mVSMC.
AIM B: Determine how selected focal adhesion proteins (a5b1 and avb3 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 Ca2+ signaling of isolated arterioles to vasoconstrictors are altered by inhibition of a5b1 or avb3 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.
These studies are relevant to our understanding of how blood vessels regulate tissue blood flow and blood pressure through attachments of smooth muscle cells to the extracellular matrix surrounding them. This information will provide new mechanistic insights directly applicable to the causes of vascular disease. This same insight will be exploitable to create new therapeutic strategies to manipulate blood vessel diameter.
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