Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth.
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)-beta1 and VEGF compared with medium conditioned by nonapoptosed EC and that TGF-beta1 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-beta1, that activate VSMC proliferation.
Sakao
Seiichiro
S
Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, 80262, USA.
Taraseviciene-Stewart
Laimute
L
Wood
Kathy
K
Cool
Carlyne D
CD
Voelkel
Norbert F
NF
D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000032:analysis; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology*; D006801:Humans; D008168:Lung / Q000098:blood supply*; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D017077:Culture Media, Conditioned; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A