HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 291/3/L362    most recent 00111.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Sakao, S. Articles by Voelkel, N. F. Search for Related Content PubMed PubMed Citation Articles by Sakao, S. Articles by Voelkel, N. F.

Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth

¹Pulmonary Hypertension Center and ²Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 10 March 2005 ; accepted in final form 6 March 2006

We have previously hypothesized that the development of severe angioproliferative pulmonary hypertension is associated with not only initial endothelial cell (EC) apoptosis followed by the emergence of apoptosis-resistant proliferating EC but also with proliferation of vascular smooth muscle cells (VSMC). We have demonstrated that EC death results in the selection of an apoptosis-resistant, proliferating, and phenotypically altered EC phenotype. We postulate here that the initial apoptosis of EC induces the release of mediators that cause VSMC proliferation. We cultured EC in an artificial capillary CellMax system designed to simulate the highly efficient functions of the human capillary system. We induced apoptosis of microvascular EC using shear stress and the combined VEGF receptor (VEGFR-1 and -2) inhibitor SU-5416. Flow cytometry for the proliferation marker bromodeoxyuridine showed that serum-free medium conditioned by apoptosed EC induced proliferation of VSMC, whereas serum-free medium conditioned by nonapoptosed EC did not. We also show that medium conditioned by apoptosed EC is characterized by increased concentrations of transforming growth factor (TGF)-1 and VEGF compared with medium conditioned by nonapoptosed EC and that TGF-1 blockade prevented the proliferation of cultured VSMC. In conclusion, EC death induced by high shear stress and VEGFR blockade leads to the production of factors, in particular TGF-1, that activate VSMC proliferation.

shear stress; vascular endothelial growth factor receptor; blockade; pulmonary microvascular endothelial cells

This article has been cited by other articles:

				V. A. de Jesus Perez, T.-P. Alastalo, J. C. Wu, J. D. Axelrod, J. P. Cooke, M. Amieva, and M. Rabinovitch Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-{beta}-catenin and Wnt-RhoA-Rac1 pathways J. Cell Biol., January 12, 2009; 184(1): 83 - 99. [Abstract] [Full Text] [PDF]

				N. Amabile, C. Heiss, W. M. Real, P. Minasi, D. McGlothlin, E. J. Rame, W. Grossman, T. De Marco, and Y. Yeghiazarians Circulating Endothelial Microparticle Levels Predict Hemodynamic Severity of Pulmonary Hypertension Am. J. Respir. Crit. Care Med., June 1, 2008; 177(11): 1268 - 1275. [Abstract] [Full Text] [PDF]

				A. L. Zaiman, M. Podowski, S. Medicherla, K. Gordy, F. Xu, L. Zhen, L. A. Shimoda, E. Neptune, L. Higgins, A. Murphy, et al. Role of the TGF-{beta}/Alk5 Signaling Pathway in Monocrotaline-induced Pulmonary Hypertension Am. J. Respir. Crit. Care Med., April 15, 2008; 177(8): 896 - 905. [Abstract] [Full Text] [PDF]

				S. Sakao, L. Taraseviciene-Stewart, C. D. Cool, Y. Tada, Y. Kasahara, K. Kurosu, N. Tanabe, Y. Takiguchi, K. Tatsumi, T. Kuriyama, et al. VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD34+ precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells FASEB J, November 1, 2007; 21(13): 3640 - 3652. [Abstract] [Full Text] [PDF]