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1 Molecular Pharmacologyand Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
2 Molecular Pharmacologyand Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Urology, Albert Einstein College of Medicine, Bronx, NY, USA; Urology, Albert Einstein College of Medicine, Bronx, NY, USA
3 Molecular Pharmacologyand Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA; Muscular and Neurodegenerative Disease Unit, University of Genova and G. Gaslini Pediatric Institute, Genova, Italy
* To whom correspondence should be addressed. E-mail: lisanti{at}aecom.yu.edu.
We have previously shown that ablation of Cav-1 gene expression in mice promotes neointimal hyperplasia in vivo, a phenomenon normally characterized by smooth muscle cell (SMC) migration and proliferation. However, it remains unknown whether these defects are cell autonomous, i.e., due to loss of Cav-1 within the smooth muscle cells themselves, or are due to loss of Cav-1 expression in other adjacent cell types in vivo. In addition, Cav-1 has been shown to associate with receptors for many vasoactive factors on the surfaces of SMCs. Therefore, Cav-1 might be an important regulator of SMC proliferation, migration, and signal transduction. To mechanistically dissect the role of Cav-1 in SMC signaling, we isolated SMCs from the aortas of Cav-1 (-/-) deficient mice. We then characterized these cells, with respect to their proliferation, migration, and calcium response to an important vasoactive factor, endothelin-1 (ET-1). Using BrdU incorporation and a wound-healing assay, Cav-1 (-/-) AoSMCs showed increased proliferation and migration rates as compared with Cav-1 (+/+) cells. In accordance with these findings, Cav-1 (-/-) AoSMCs demonstrated an upregulation of phospho-ERK1/2, Cyclin D1, and PCNA, as well as reduced expression of the cdk inhibitor, p27Kip1. The Ca2+ response was examined in the presence of ET-1 and was assessed by confocal microscopy, using a Ca2+-sensitive fluorescent probe, Fluo-3. When treated with ET-1, Cav-1 (-/-) AoSMCs exhibited a faster and higher increase in free intracellular Ca2+ than Cav-1 (+/+) cells. Moreover, the ET-1-induced response in Cav-1 (-/-) cells was mediated by the ETB receptor, as shown using receptor antagonists (BQ788, an ETB antagonist versus BQ123, an ETA antagonist). Finally, Cav-1 (-/-) cells showed reduced expression of the ETA receptor, and upregulation of the ETB. Therefore, Cav-1 ablation increased the calcium response in SMCs induced by ET-1, by altering the type and expression level of the ET receptor (i.e., receptor isoform switching). Taken together, these data suggest a novel regulatory role for Cav-1 in SMCs with respect to their proliferation, migration, as well as a Ca2+-signaling.
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