Background: The growth-promoting effect of mechanical stress on vascular smooth muscle cells (VSMC) has been implicated in the progress of cardiovascular diseases related to elevated blood pressure. The underlying molecular mechanisms are, however, not completely defined.
Methods: We have studied primary human aortic VSMC using a model for multilateral stretch. Expression of the suppressor of cytokine signaling (SOCS) family member SOCS-1 and related molecular mechanisms were studied using TaqMan analysis, immunoblotting, protein silencing, specific cell treatment, immunoprecipitation and immunocytochemistry.
Results: Mechanical stretch inhibits SOCS-1 mRNA and protein expression. This effect was abolished by cell treatment with methyl-beta-cyclodextrin disrupting lipid rafts and with RGD peptide affecting integrins. Inhibition of integrin interaction with another cellular receptor, urokinase receptor (uPAR), as well as uPAR silencing also abolished stretch-induced SOCS-1 downregulation. Mechanical stretch resulted in uPAR redistribution to lipid rafts and in its colocalization with focal adhesion kinase (FAK). Stretch impairs polyubiquitination and proteosomal degradation of FAK leading to FAK upregulation in stretched VSMC. SOCS-1 silencing and inhibition of proteosomal degradation simulate this effect.
Conclusion: Our study identifies SOCS-1 as a novel participant involved in the propagation of mechanical stimuli in human VSMC, which might be relevant for the development of cardiovascular diseases.