Mechanical strain and physical deformation is a prominent feature of the environment of arterial vascular smooth muscle (VSM) cells in situ. In hypertension, in which strain increases, there are numerous alterations in the growth, hormonal responsiveness, and biochemical phenotype of the VSM cell. These vascular changes are responsible for end-organ damage in hypertension and may play a role in the development of accelerated, malignant hypertension. Despite the potential importance of mechanical strain in causing phenotypic changes in the VSM cell, strain has largely been ignored in previous research on the biology of the VSM cell. This is because, unlike the native blood vessel, the substrate used in current in vitro culture technology (plastic) does not stretch. As the basis for the proposed studies, we hypothesize that mechanical strain plays a critical role in the growth and phenotype of vascular smooth muscle cells. VSM -cells have been cultured in our lab on flexible supports to which mechanical strain can be applied. Preliminary data show that strain induces VSM cells to synthesize DNA and to proliferate and that this response is dependent upon the type of extracellular matrix with which the flexible supports are coated. The response is blocked by peptides which prevent interactions with the matrix. The mechanism by which this growth response is produced is via autocrine secretion of the A- and B- chains of PDGF. The proposed studies are designed to examine l) the mechanism by which the extracellular matrix signals the information of strain to the cell, 2) whether or not alterations in ion transport are involved in the signaling of mechanical strain, 3) the mechanisms by which strain induces transcription of the genes for the A- and B- chains of PDGF, and 4) whether or not there are differences in the sensing of strain by neonatal and adult vascular smooth muscle cells. The methods to be used are: l) Preparation of cultured VSM cells from neonatal and adult rats, 2) Culture of these cells on deformable surfaces to which various extra-cellular matrix proteins can be applied, 3) Measurements of ion transport in cells exposed to strain, 4) measurement of transcriptional activity of PDGF A- and B- chain promoter truncations by the use of reporter genes.
| Ma, Y H; Ling, S; Ives, H E (1999) Mechanical strain increases PDGF-B and PDGF beta receptor expression in vascular smooth muscle cells. Biochem Biophys Res Commun 265:606-10 |
| Morawietz, H; Ma, Y H; Vives, F et al. (1999) Rapid induction and translocation of Egr-1 in response to mechanical strain in vascular smooth muscle cells. Circ Res 84:678-87 |
| Wilson, E; Vives, F; Collins, T et al. (1998) Strain-responsive regions in the platelet-derived growth factor-A gene promoter. Hypertension 31:170-5 |
| Reusch, P; Wagdy, H; Reusch, R et al. (1996) Mechanical strain increases smooth muscle and decreases nonmuscle myosin expression in rat vascular smooth muscle cells. Circ Res 79:1046-53 |
