Unresolved mechanisms: a hypothesized spatial regulation of myosin light chain phosphorylation within the walls of resistance arteries

Myosin light chain (MLC) phosphorylation is a fundamental determinant of vascular smooth muscle contraction. While its biochemical regulation has been well-studied, the spatial control of MLC phosphorylation within the vessel wall is less well understood. We recently identified a transmural gradient of phosphorylated MLC (pMLC) across the wall of rat superior cerebellar arteries, with levels peaking in outer-layer (i.e. adventitially directed) vascular smooth muscle cells (VSMCs). This finding suggests that the maintenance of vascular tone may involve spatially heterogeneous contractile signaling at the level of pMLC. We hypothesize that wall tension and consequent mechanotransduction processes to be the primary drivers of this pMLC gradient, potentially through pathways involving adhesion receptors (integrins, N-cadherin), mechanosensitive ion channels, and force-sensitive G protein-coupled receptors in outer-layer VSMCs. In addition, diffusion-limited gradients of endothelium-derived relaxing factors, including nitric oxide and prostacyclin, may establish a counter-gradient of relaxation, strongest at the inner vessel wall. The convergence of these spatially opposing signals-outer-layer mechanotransduction and inner-layer chemical relaxation-conceivably fine-tunes wall tension and stabilizes vascular tone. The proposed hypothesis is generated from evidence supporting this model of spatially regulated MLC phosphorylation as a fundamental mechanism for tension homeostasis in resistance arteries.