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1 University of Colorado Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine, Denver, Colorado, United States
2 Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado, United States
3 Department of Pathology, University of Colorado Health Sciences Center, Division of Pulmonary Sciences and Critical Care Medicine, Denver, Colorado, United States
4 Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, United States
* To whom correspondence should be addressed. E-mail: norbert.voelkel{at}uchsc.edu.
We have previously hypothesized that the development of severe angioproliferative pulmonary hypertension (SAPH) is associated not only with initial endothelial cell apoptosis followed by the emergence of apoptosis-resistant proliferating endothelial cells, but also with proliferation of vascular smooth muscle cells (VSMC). We have demonstrated that endothelial cell (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 which cause VSMC proliferation. We cultured EC in a unique artificial capillary CellMax system designed to simulate the highly efficient functions of the human capillary system. We induced apoptosis of microvascular endothelial cells using shear stress and the combined vascular endothelial cell factor (VEGF) receptor VEGFR-I and II inhibitor SU5416. Flow cytometry for the proliferation marker BrdU showed that serum-free medium conditioned by apoptosed EC induced proliferation of VSMC while serum-free medium conditioned by non-apoptosed EC did not. We also show that medium conditioned by apoptosed EC is characterized by increased concentrations of TGF-
1 and VEGF compared with medium conditioned by non-apoptosed EC and that TGF-1 blockade prevented the proliferation of cultured VSMC.
In conclusion, endothelial cell death induced by high shear stress and VEGF receptor blockade leads to the production of factors, in particular TGF-1, which activate VSMC proliferation.
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