PECAM-1 mediates NO-dependent dilation of arterioles to high temporal gradients of shear stress.

OBJECTIVE: In response to changes in wall shear stress (WSS) the vascular endothelium releases several factors, among others nitric oxide. On the basis of studies of endothelial cells in culture, suggesting that platelet endothelial cell adhesion molecule-1 (PECAM-1) is specifically involved in sensing and coupling high temporal gradients of fluid shear stress with activation of eNOS, we hypothesized that dilations of isolated skeletal muscle arterioles from PECAM-1 knockout mice (PECAM-KO) will be reduced to rapid increases in WSS elicited by increases in perfusate flow. METHODS AND RESULTS: Small and large step increases in flow resulted in substantial dilations in arterioles of WT mice (45+/-4%), but they were markedly reduced in arterioles of PECAM-KO mice (22+/-5%). The initial slope of dilations, when WSS increased rapidly, was greater in vessels of WT than those of PECAM-KO mice (slopes: 0.378 and 0.094, respectively), whereas the second phase of dilations, when flow/shear stress was steady, was similar in the 2 groups (slopes: 0.085 and 0.094, respectively). Inhibition of eNOS significantly reduced the initial phase of dilations in arterioles from WT, but not from those of PECAM-KO mice. The calcium ionophore A23187 elicited similar NO-mediated dilation in both WT and PECAM-KO mice. CONCLUSIONS: In isolated arterioles of PECAM-KO mice activation of eNOS and consequent dilation by agonists is maintained, but the dilation to high temporal gradients of wall shear stress elicited by increases in perfusate flow is reduced. Thus, we propose that PECAM-1 plays an important role in the ability of the endothelium to sense and couple high temporal gradients of wall shear stress to NO-mediated arteriolar dilation during sudden changes in blood flow in vivo

Mechanotransduction and Vascular Resistance

International audienceMechanotransduction is the process by which any cell transduces (converts) a mechanical signal into chemical cues. The vessel wall is permanently sheared by the moving blood particles as well as stretched and compressed by the pressure applied by the blood. Multiple types of mechanical stress fields are associated with flow patterns and unsteadiness.Mechanosensing occurs locally at the plasma membrane. It relies on detection of local changes in protein conformation that lead to ion channel opening, protein unfolding, modified enzyme kinetics, and variations in molecular interactions following exposure of buried binding site or, conversely, hiding them.Mechanotransduction initiates several signaling pathways. Multiple mediators include: At the cell surface, G-protein-coupled and protein tyrosine kinase receptors, ion channels, enzymes, adhesion molecules, and specialized plasmalemmal nanodomains At the cell cortex, the cortical actin network that regulates the cell-surface mechanics and signaling adaptors and effectors (e.g., small monomeric guanosine triphosphatases and heterotrimeric guanine nucleotide-binding proteins, kinases, phosphatases, and ubiquitins, among others) In the cytosol, enzymes, scaffolds, carriers such as endosomes, calcium concentration, and transcription factors In the nucleus, nuclear pore carriers, enzymes, and the transcriptional and translational machineryMechanotransduction by vascular cells regulate the contraction–relaxation state of vascular smooth myocytes, thereby regulating locally and quickly the size of the vascular lumen, that is, the local vascular resistance to blood flow. Once experiencing an unusual mechanical stress, vascular smooth myocytes react by contracting or relaxing according to the magnitude of the mechanical stress, the value of which rises above or falls below the range in which it fluctuates in normal conditions. Moreover, they receive chemical and electrochemical signals from endotheliocytes, themselves sensing the wall shear stress at their wetted (luminal) surface.Mechanotransduction thus regulates locally blood flow more rapidly than the endocrine regulation by remote tissues and even than that of the nervous system, which transmits signals very rapidly via afferent nerves and, after processing in the centers of the spinal cord and brain, efferent nerves