Mechanisms of stretch-induced growth and contractile differentiation in vascular smooth muscle
Sammanfattning: Vascular smooth muscle can adapt to increased intraluminal pressure by remodelling and hypertrophy, as seen in hypertension. The molecular mechanisms responsible for this are still incompletely characterized. We have developed an organ culture system where strips of rat or mouse portal veins are cultured for 1 to 3 days loaded (stretched) by an attached weight and then studied for morphology, function and biochemical composition. Contractility, tissue weight, protein- and DNA synthesis were all greater compared with unloaded veins. The signalling mechanisms include autocrine effects of endogenously released angiotensin II and endothelin-1 and activation of the MAP kinases ERK 1/2. The growth-promoting effects of stretch and endothelin-1, but not angiotensin II, depend on cholesterol-rich membrane domains (caveolae). Inhibitors of RhoA/Rho kinase and of actin polymerisation decreased stretch-induced growth. Protein synthesis was analysed by autoradiography following gel electrophoresis and showed that stretch promotes the synthesis of contractile and cytoskeletal proteins known to be markers for the contractile phenotype of smooth muscle, e.g. a- and g- actin, the actin associated proteins tropomyosin, calponin and SM22a, and intermediate filament proteins. Synthesis of SM22a and actin was reduced by inhibition of RhoA, ERK1/2, and angiotensin II receptor-1, while inhibition of Rho kinase had no effect. Resistance arteries and portal veins from SM22a-deficient mice showed decreased contractility and actin contents, suggesting a role of this protein in actin filament structure and function. Stretch-induced protein synthesis was unaffected by SM22a ablation. Stretch stimulates growth and differentiation of smooth muscle cells in the vessel wall in a maintained contractile phenotype, in contrast to the growth stimulation in a synthetic non-contractile phenotype seen in vessel injury and atherosclerosis.
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