Published ahead of print on February 28, 2008, doi:10.1165/rcmb.2007-0283OC Am. J. Respir. Cell Mol. Biol., Volume 39, Number 1, July 2008, 105-112 A more recent version of this article appeared on July 1, 2008
Submitted on July 25, 2007 Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell GrowthCristhiaan D Ochoa1*,1 Department of Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA, 2 Department of Chemistry and Chemical Biology, Northeastern University, Barnett Institute, Boston, MA, USA, 3 Department of Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Anesthesia and Critical Care, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA * To whom correspondence should be addressed. E-mail: cdo701{at}jaguar1.usouthal.edu.
Background: Endothelial cells are subjected to mechanical forces in the form of cyclic stretch resulting from blood pulsatility. Pulmonary artery endothelial cells (PAEC) have been found to produce factors that stimulate and inhibit pulmonary artery smooth muscle cell (PASMC) growth. We hypothesized that PAEC exposed to cyclic stretch would secrete proteins that inhibit PASMC growth. Methods and Results: Media from PAEC exposed to cyclic stretch significantly inhibited PASMC growth in a time-dependent manner. Lyophilized material isolated from stretched PAEC conditioned media significantly inhibited PASMC growth in a dose-dependent manner. This inhibition was reversed by trypsin inactivation; a finding consistent with the relevant factor being a protein(s). To identify proteins that inhibited cell growth in conditioned media from stretched PAEC, we employed proteomic techniques and found that thrombospondin-1 (TSP-1); a natural antiangiogenic factor was upregulated by stretch. In vitro, exogenous TSP-1 inhibited PASMC growth. TSP-1 blocking antibodies reversed conditioned media -induced inhibition of PASMC growth. Conclusions: Cyclic stretched PAEC secrete protein(s) that inhibit PASMC proliferation. TSP-1 may be, at least in part, responsible for this inhibition. The complete identification and understanding of the secreted proteome of stretched PAEC may lead to new insights into the pathophysiology of pulmonary vascular remodeling.
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