Pressure-induced (myogenic) vasoconstriction is key to setting of peripheral resistance and autoregulation of blood flow. Myogenic constriction depends on smooth muscle (SM) membrane depolarization and voltage- dependent Ca2+-influx. Although myogenic responsiveness is an inherent property of arteriolar SM, it is modulated by hyperpolarizing and vasodilator influences. An important mediator of a number of vasodilator stimuli in SM is the Ca2+-sensitive large-conductance K+ ion channel (BKCa). Activation of BKCa by depolarization and increased intracellular [Ca2+] has been proposed to serve as a 'feedback'inhibitor, preventing excessive myogenic constriction of arterioles as intralumenal pressure increases. This hypothesis is largely based on studies performed in small cerebral arteries, however our work does not support an identical role for BKCa in regulating myogenic tone of skeletal muscle arterioles, which are a major contributor to peripheral resistance. Interestingly, our studies suggest a fundamental difference between skeletal muscle arterioles and small cerebral arteries in the relationship between SM membrane potential and pressure-induced constriction suggesting that in skeletal muscle vessels BKCa activation may be minimized to allow sustained vasoconstriction under resting conditions. The overall goals of the studies in this proposal are to define the physiological role and mechanisms of regulation for BKCa in arteriolar SM of skeletal muscle. Control of BKCa is complex with regulation occurring at the molecular and post-translational levels as well as by its cellular location with respect to other signaling-related molecules. This complexity of regulation provides extensive opportunity for tissue-specific heterogeneity where channel behavior is matched to local tissue requirements. Thus, our overall hypothesis is that BKCa is differentially regulated in vascular SM from cerebral and skeletal muscle. Further, such regional differences in regulation of BKCa allow for local control of hemodynamics to be appropriately matched to tissue function. Using a combination of molecular, cellular and electrophysiological approaches, in skeletal muscle and cerebral vascular preparations, the proposed studies aim to: 1. examine subunit composition and expression of BKCa;2. test the role of BKCa subunits in modulating myogenic constriction using an siRNA knockdown approach;3. define mechanisms of BKCa regulation in isolated SM cells with emphasis on Ca2+ and voltage sensitivity;modulation by cGMP/cGMP-dependent protein kinase;4. test the role of BKCa in modulating myogenic tone of isolated vessels, focusing on both feedback-modulation of tone and the sensitivity of the BKCa channel to cGMP/cGMP- dependent protein kinase and vasodilator mechanisms activating this second messenger system. Understanding tissue-specific mechanisms by which BKCa function is regulated will impact on design and utilization of channel modulators developed as therapeutic measures for treatment of vascular diseases.
This study will improve our knowledge of how small arteries can vary their diameters and thus control local blood flow. Importantly, the data obtained will also contribute to identifying biochemical sites that may be altered in pathophysiological situations. Thus the potential exists for the identification of steps in cellular signaling that may ultimately be used for the targeting of pharmacological therapies.
|Sehgel, Nancy L; Sun, Zhe; Hong, Zhongkui et al. (2015) Augmented vascular smooth muscle cell stiffness and adhesion when hypertension is superimposed on aging. Hypertension 65:370-7|
|Chen, Xiuping; Zhang, Hanrui; Hill, Michael A et al. (2015) Regulation of Coronary Endothelial Function by Interactions between TNF-Î±, LOX-1 and Adiponectin in Apolipoprotein E Knockout Mice. J Vasc Res 52:372-82|
|Lee, Sewon; Yang, Yan; Tanner, Miles A et al. (2015) Heterogeneity in Kv7 channel function in the cerebral and coronary circulation. Microcirculation 22:109-21|
|Mishra, Ramesh C; Wulff, Heike; Hill, Michael A et al. (2015) Inhibition of Myogenic Tone in Rat Cremaster and Cerebral Arteries by SKA-31, an Activator of Endothelial KCa2.3 and KCa3.1 Channels. J Cardiovasc Pharmacol 66:118-27|
|Nourian, Zahra; Li, Min; Leo, M Dennis et al. (2014) Large conductance Ca2+-activated K+ channel (BKCa) Î±-subunit splice variants in resistance arteries from rat cerebral and skeletal muscle vasculature. PLoS One 9:e98863|
|Dora, Kim A; Hill, Michael A (2013) Measurement of changes in endothelial and smooth muscle CaÂ²âº in pressurized arteries. Methods Mol Biol 937:229-38|
|Yang, Yan; Sohma, Yoshiro; Nourian, Zahra et al. (2013) Mechanisms underlying regional differences in the Ca2+ sensitivity of BK(Ca) current in arteriolar smooth muscle. J Physiol 591:1277-93|
|Hill, Michael A; Meininger, Gerald A (2012) Arteriolar vascular smooth muscle cells: mechanotransducers in a complex environment. Int J Biochem Cell Biol 44:1505-10|
|Clifford, Philip S; Ella, Srikanth R; Stupica, Aaron J et al. (2011) Spatial distribution and mechanical function of elastin in resistance arteries: a role in bearing longitudinal stress. Arterioscler Thromb Vasc Biol 31:2889-96|
|Ella, Srikanth R; Yang, Yan; Clifford, Philip S et al. (2010) Development of an image-based system for measurement of membrane potential, intracellular Ca(2+) and contraction in arteriolar smooth muscle cells. Microcirculation 17:629-40|
Showing the most recent 10 out of 14 publications