Cellular signalling in arteriolar myogenic constriction: involvement of tyrosine phosphorylation pathways.
1. An increase in transmural pressure in arterioles results in a shortening of vascular smooth muscle cells, with subsequent constriction of the vessel. The mechanisms underlying this myogenic contraction are not fully understood; however, the obligatory role of increases in intracellular [Ca(2+)] and myosin light chain phosphorylation have been demonstrated. 2. The myogenic response shows a relationship with smooth muscle cell membrane potential and influx of extracellular Ca(2+) through voltage-operated Ca(2+) channels (VOCC). Mechanically sensitive channels and possibly release of Ca(2+) from intracellular stores may play a role. However, there are other components of myogenic contraction that cannot be explained by a Ca(2+)-MLCK mechanism, for example the initial sensing of alterations in transmural pressure, whether sustained myogenic constriction involves myofilament Ca(2+) sensitization or remodelling of the vessel wall in response to a maintained increase in transmural pressure. 3. In an attempt to investigate these areas, recent studies have examined a role for tyrosine phosphorylation pathways in pressure-induced contraction of arterioles. In rat pressurized cremaster arterioles, tyrosine kinase inhibitors dilated vessels showing spontaneous myogenic tone and tyrosine phosphatase inhibitors caused vasoconstriction. However, pressure-induced myogenic constriction of vessels persisted in the presence of these agents. Biochemical studies revealed that phosphotyrosine formed at a relatively slow rate (significant after 5 min, with maximal increase after approximately 15 min) in response to increased vessel transmural pressure, in contrast with myosin light chain phosphorylation or the time-course of myogenic constriction itself (maximum within 1 min). 4. Taken together, these observations support the idea of a role for tyrosine phosphorylation pathways in longer-term responses to increased transmural pressure rather than acute myogenic constriction. Phosphotyrosine formation was also more closely correlated to vessel wall tension (pressure x diameter) than the diameter of the arterioles alone. The identity of the tyrosine-phosphorylated proteins requires further investigation; however, there is some evidence supporting roles for cSrc-type tyrosine kinases and p44 mitogen-activated protein kinase. The longer-term responses of blood vessels to increased transmural pressure that may involve tyrosine phosphorylation pathways include maintenance of myogenic constriction and vessel wall remodelling.
Murphy
Timothy V
TV
Microvascular Biology Group, School of Medical Sciences, RMIT University, Melbourne, Victoria, Australia. t.murphy@rmit.edu.au
Spurrell
Brian E
BE
Hill
Michael A
MA
D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D051381:Rats; D014443:Tyrosine / Q000378:metabolism*; D014661:Vasoconstriction / Q000502:physiology*
D014443:Tyrosine