Intrinsic regulation of microvascular tone by myoendothelial feedback circuits.

Abstract

The endothelium is an important regulator of arterial vascular tone, acting to release nitric oxide (NO) and open Ca²⁺-activated K⁺ (K_Ca) channels to relax vascular smooth muscle cells (VSMCs). While agonists acting at endothelial cell (EC) receptors are widely used to assess the ability of the endothelium to reduce vascular tone, the intrinsic EC-dependent mechanisms are less well characterized. In small resistance arteries and arterioles, the presence of heterocellular gap junctions termed myoendothelial gap junctions (MEGJs) allows the passage of not only current, but small molecules including Ca²⁺ and inositol trisphosphate (IP₃). When stimulated to contract, the increase in VSM Ca²⁺ and IP₃ can therefore potentially pass through MEGJs to activate adjacent ECs. This activation releases NO and opens K_Ca channels, which act to limit contraction. This myoendothelial feedback (MEF) is amplified by EC Ca²⁺ influx and release pathways, and is dynamically modulated by processes regulating gap junction conductance. There is a remarkable localization of key signaling and regulatory proteins within the EC projection toward VSM, and the intrinsic EC-dependent signaling pathways occurring with this highly specialized microdomain are reviewed.