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A protein kinase G-sensitive channel mediates flow-induced Ca²⁺ entry into vascular endothelial cells

X. YAO^*1, H. Y. KWAN^*, F. L. CHAN, N. W. K. CHAN^* and Y. HUANG^*

^* Department of Physiology,
Department of Anatomy, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong

¹Correspondence: 319 BMSB, Department of Physiology, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong. E-mail: yao2068{at}cuhk.edu.hk

The hemodynamic force generated by blood flow is considered to be the physiologically most important stimulus for the release of nitric oxide (NO) and prostacyclin (PGI₂) from vascular endothelial cells (1). NO and PGI₂ then act on the underlying smooth muscle cells, causing vasodilation and thus lowering blood pressure (2, 3). One critical early event occurring in this flow-induced regulation of vascular tone is that blood flow induces Ca²⁺ entry into vascular endothelial cells, which in turn leads to the formation of NO (4, 5). Here we report a mechanosensitive Ca²⁺-permeable channel in vascular endothelial cells. The activity of the channel was inhibited by 8-Br-cGMP, a membrane-permeant activator of protein kinase G (PKG), in cell-attached membrane patches. The inhibition could be reversed by PKG inhibitor KT5823 or H-8. A direct application of active PKG in inside-out patches blocked the channel activity. Gd³⁺, Ni²⁺, or SK&F-96365 also inhibited the channel activity. A study of fluorescent Ca²⁺ entry revealed a striking pharmacological similarity between the Ca²⁺ entry elicited by flow and the mechanosensitive Ca²⁺-permeable channel we identified, suggesting that this channel is the primary pathway mediating flow-induced Ca²⁺ entry into vascular endothelial cells.—Yao, X., Kwan, H. Y., Chan, F. L., Chan, N. W. K., Huang, Y. A protein kinase G-sensitive channel mediates flow-induced Ca²⁺ entry into vascular endothelial cells.

Key Words: blood flow • shear stress • nonselective cation channel • endothelium

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