Contribution of Kv7.4/Kv7.5 Heteromers to Intrinsic and Calcitonin Gene-Related Peptide–Induced Cerebral Reactivity

作者：Preet S. Chadha, Thomas A. Jepps, Georgina Carr, Jennifer B. Stott, Hei-Lei Zhu, William C. Cole, Iain A. Greenwood · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2014 · DOI：10.1161/atvbaha.114.303405 · 被引用次数：90 · 研究领域：Cerebrovascular and Carotid Artery Diseases、Barrier Structure and Function Studies、Protease and Inhibitor Mechanisms

OBJECTIVE: Middle cerebral artery (MCA) diameter is regulated by inherent myogenic activity and the effect of potent vasodilators such as calcitonin gene-related peptide (CGRP). Previous studies showed that MCAs express KCNQ1, 4, and 5 potassium channel genes, and the expression products (Kv7 channels) participate in the myogenic control of MCA diameter. The present study investigated the contribution of Kv7.4 and Kv7.5 isoforms to myogenic and CGRP regulation of MCA diameter and determined whether they were affected in hypertensive animals. APPROACH AND RESULTS: Isometric tension recordings performed on MCA from normotensive rats produced CGRP vasodilations that were inhibited by the pan-Kv7 channel blocker linopirdine (P<0.01) and after transfection of arteries with siRNA against KCNQ4 (P<0.01) but not KCNQ5. However, isobaric myography revealed that myogenic constriction in response to increases in intravascular pressure (20-80 mm Hg) was affected by both KCNQ4 and KCNQ5 siRNA. Proximity ligation assay signals were equally abundant for Kv7.4/Kv7.4 or Kv7.4/Kv7.5 antibody combinations but minimal for Kv7.5/Kv7.5 antibodies or Kv7.4/7.1 combinations. In contrast to systemic arteries, Kv7 function and Kv7.4 abundance in MCA were not altered in hypertensive rats. CONCLUSIONS: This study reveals, for the first time to our knowledge, that in cerebral arteries, Kv7.4 and Kv7.5 proteins exist predominantly as a functional heterotetramer, which regulates intrinsic myogenicity and v...