Smooth muscle cell growth and tissue remodeling

Hollow organs such as the heart, bladder and vasculature are constantly exposed to a range of mechanical stimuli (e.g., pressure, increased tension, shear stress). We are interested in the molecular mechanisms by which mechanical force, such as stretch and pressure, can be converted into biochemical information. This process of “mechanotransduction” is believed to underlie the pathologic tissue remodeling associated with a number of diseases, such as cardiac and bladder hypertrophy. Because the heart and urinary bladder are both hollow organs that respond to increased resistance to flow by inducing tissue growth, we are working to determine how similar—or distinct—are the pathways of mechanotransduction in both tissues. These studies are directed toward a better understanding of the molecular basis of congenital syndromes in children, such as posterior urethal valves, and in age-related urinary tract conditions in adults.

Selected publications

Park, J.M., Borer, J.G., Freeman, M.R., and Peters, C.A. (1998) Stretch activates heparin-binding EGF-like growth factor expression in bladder smooth muscle cells. American Journal of Physiology 275: (Cell Physiol. 44): C1247-C1254.

Park, J.M., Yang, T., Arend, L.J., Schnermann, J.B., Peters, C.A., Freeman, M.R., and Briggs, J. (1999) Obstruction stimulates COX-2 expression in bladder smooth muscle cells via increased mechanical stretch. American Journal of Physiology 276 (Renal Physiol. 45):F129-F136. (Cover art)

Park, J.M., Adam, R.M., Peters, C.A., Guthrie, P.D., Sun, Z., Klagsbrun, M., and Freeman, M.R. (1999) AP-1 mediates stretch-induced expression of heparin-binding EGF-like growth factor in bladder smooth muscle cells. American Journal of Physiology (Cell Physiol.) C294-301.

Borer, J.G., Park, J.M., Atala, A., Nguyen, H.T., Adam, R.M., Retik, A.B., Freeman, M.R. (1999) Heparin-binding EGF-like growth factor expression increases selectively in bladder smooth muscle in response to lower urinary tract obstruction. Laboratory Investigation 79:1335-1345.

Nguyen, H.T., Adam, R.M., Bride, S.H., Park, J.M., Peters, C.A., and Freeman, M.R. (2000) Cyclic stretch activates p38 SAPK2-, ErbB2- and AT1-dependent signaling in bladder smooth muscle cells. American Journal of Physiology (Cell Physiol.) 279:C1155-C1167.

Stehr, M., Adam, R.M., Khoury, J., Zhuang, L., Solomon, K.R., Peters, C.A., and Freeman, M.R. (2003) Platelet-derived growth factor-BB is a potent mitogen for rat ureteral and human bladder smooth muscle cells: dependence on lipid rafts for cell signaling. Journal of Urology 169:1165-1170.

Danciu, T.E., Adam, R.M., Naruse, K., Freeman, M.R., and Hauschka, P.V. (2003) Calcium regulates the PI3K-Akt pathway in stretched osteoblasts. FEBS Letters 536:193-197.

Adam, R.M., Roth, J.A., Cheng, H-L., Rice, D.C., Khoury, J., Bauer, S.B., Peters, C.A., and Freeman, M.R. (2003) Signaling through PI3K-Akt mediates stretch- and PDGF-BB-dependent DNA synthesis in bladder smooth muscle cells. Journal of Urology 169:2388-2393.

Stehr, M., Estrada, C., Khoury, J., Danciu, T., Sullivan, M.P., Peters, C.A., Solomon, K.R., Freeman, M.R. and Adam, R.M. (2004) Caveolae are negative regulators of TGF b 1 signaling in ureteral smooth muscle cells. Journal of Urology 172:2451-2455.

Adam, R.M., Eaton, S.H., Estrada, C., Nimgaonkar, A., Shih-S-C, Smith, L.E.H., Kohane, I.S., Bagli, D, and Freeman, M.R. (2004) Mechanical stretch is a highly selective regulator of gene expression in human bladder smooth muscle cells. Physiological Genomics 20:36-44.

Orsala, A., Estrada, C.R., Nguyen, H.T., Retik, A.B., Freeman, M.R., Peters, C.A. and Adam, R.M. (2005) Growth and stretch response of human exstrophy bladder smooth muscle cells: Molecular evidence of normal intrinsic function. BJU, International (British Journal of Urology). 95:144-148.

MacLellan, D.L., Steen, H., Adam, R.M., Garlick, M., Zurakowski, D., Gygi, S.P., Freeman, M.R. and Solomon, K.R. (2005) A quantitative proteomic analysis of growth factor-induced compositional changes in lipid rafts of human smooth muscle cells. Proteomics 5:4733-4742.

top