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
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.
|Korthuis, Ronald J (2018) Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction. Adv Pharmacol 81:331-364|
|Sun, Zhe; Li, Min; Li, Zhaohui et al. (2017) N-Cadherin, a novel and rapidly remodelling site involved in vasoregulation of small cerebral arteries. J Physiol 595:1987-2000|
|Hong, Kwangseok; Li, Min; Nourian, Zahra et al. (2017) Angiotensin II Type 1 Receptor Mechanoactivation Involves RGS5 (Regulator of G Protein Signaling 5) in Skeletal Muscle Arteries: Impaired Trafficking of RGS5 in Hypertension. Hypertension 70:1264-1272|
|Dai, Hongyan; Wang, Meifang; Patel, Parag N et al. (2017) Preconditioning with the BKCa channel activator NS-1619 prevents ischemia-reperfusion-induced inflammation and mucosal barrier dysfunction: roles for ROS and heme oxygenase-1. Am J Physiol Heart Circ Physiol 313:H988-H999|
|Foote, Christopher A; Castorena-Gonzalez, Jorge A; Staiculescu, Marius C et al. (2016) Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization. Am J Physiol Heart Circ Physiol 310:H188-98|
|Higashi, Yusuke; Sukhanov, Sergiy; Shai, Shaw-Yung et al. (2016) Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E-Deficient Mice. Circulation 133:2263-78|
|Kalogeris, Theodore; Baines, Christopher P; Krenz, Maike et al. (2016) Ischemia/Reperfusion. Compr Physiol 7:113-170|
|Hong, Kwangseok; Zhao, Guiling; Hong, Zhongkui et al. (2016) Mechanical activation of angiotensin II type 1 receptors causes actin remodelling and myogenic responsiveness in skeletal muscle arterioles. J Physiol 594:7027-7047|
|Wang, Derek Z; Jones, Allan W; Wang, Walter Z et al. (2016) Soluble guanylate cyclase activation during ischemic injury in mice protects against postischemic inflammation at the mitochondrial level. Am J Physiol Gastrointest Liver Physiol 310:G747-56|
|Manrique, Camila; Habibi, Javad; Aroor, Annayya R et al. (2016) Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice. Cardiovasc Diabetol 15:94|
Showing the most recent 10 out of 56 publications