Arteriolar myogenic signalling mechanisms: Implications for local vascular function.

Abstract

Arterioles typically exist in a state of partial constriction that is related to the level of intraluminal pressure. This vasomotor response is a function of the vascular smooth muscle and occurs independently of neurohumoral and endothelial input. The physiological relevance of myogenic constriction relates to the setting of peripheral resistance, provision of a level of tone that vasodilators can access, and a contribution to control of capillary pressure. Despite its importance in the regulation of microvascular haemodynamics the exact cellular mechanisms linking intraluminal pressure to myogenic constriction remain uncertain. Studies using isolated, cannulated arteriole techniques, and freshly dispersed smooth muscle cells, have shown that increased intraluminal pressure/cell stretch leads to smooth muscle cell membrane depolarisation, the opening of L-type voltage-gated Ca2+ channels (VGCC), Ca2+-dependent activation of myosin light chain kinase and actomyosin-based contraction. Questions remain as to how the initial stimulus is detected and how these events lead to membrane depolarisation. A candidate pathway for the mechanosensory events involves the link between extracellular matrix proteins, cell surface integrins and the subsequent activation of intracellular signalling events. Membrane depolarisation may occur through the involvement of various ion channels, including non-selective cation channels (possibly themselves mechanosensitive) that predominantly pass Na+ from the extracellular space. Evidence suggests that this may involve TRP-like channels, possibly TRPM4 or TRPC6 isoforms that are modulated by diacylglycerol and protein kinase C. In addition, the exact roles played by various Ca2+ pools, including those occurring in spatially-restricted domains, and Ca2+ sensitisation, remain uncertain despite the clearly important role of VGCC. Similarly, while a change in intraluminal pressure is associated with the generation of a number of second messengers and the activation of various protein kinases, their roles in myogenic contraction versus long-term adaptive responses, such as tissue remodelling, are still to be defined.