This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 2007-0283OCv1 39/1/105    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Ochoa, C. D. Articles by Quinn, D. A. Search for Related Content PubMed PubMed Citation Articles by Ochoa, C. D. Articles by Quinn, D. A.

Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell Growth

¹ Pulmonary and Critical Care Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and ² Barnett Institute, Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts

Correspondence and requests for reprint should be addressed to Cristhiaan D. Ochoa, M.D., Pulmonary and Critical Care Unit, Massachusetts General Hospital, Bullfinch 148, 55 Fruit Street, Boston, MA 02114. E-mail: cdo701{at}jaguar1.usouthal.edu

Endothelial cells are subjected to mechanical forces in the form of cyclic stretch resulting from blood pulsatility. Pulmonary artery endothelial cells (PAECs) produce factors that stimulate and inhibit pulmonary artery smooth muscle cell (PASMC) growth. We hypothesized that PAECs exposed to cyclic stretch secrete proteins that inhibit PASMC growth. Media from PAECs 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, which is consistent with the relevant factor being a protein(s). To identify proteins that inhibited cell growth in conditioned media from stretched PAECs, we used proteomic techniques and found that thrombospondin (TSP)-1, a natural antiangiogenic factor, was up-regulated by stretch. In vitro, exogenous TSP-1 inhibited PASMC growth. TSP-1–blocking antibodies reversed conditioned media–induced inhibition of PASMC growth. Cyclic stretched PAECs 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 PAECs may lead to new insights into the pathophysiology of pulmonary vascular remodeling.

Key Words: pulmonary endothelium • smooth muscle cells growth • cyclic stretch • proteomics • thrombospondin-1

CLINICAL RELEVANCE These observations are important for understanding the pathophysiology of pulmonary vascular disease, since most studies of endothelial biology have been performed on static cultures; under physiological conditions, however, the endothelium is not motionless.