01 March 2017 by Andriy Samokhin

Endothelial exosomes induced by aldosterone increase fibrillar collagen levels in pulmonary artery smooth muscle cells

Elevated levels of the hormone aldosterone (ALDO) are implicated in the pathobiology of vascular fibrosis in pulmonary arterial hypertension (PAH). We have demonstrated previously that human pulmonary artery endothelial cell (HPAEC) treatment with ALDO upregulates fibrosis proteins in co-cultured human pulmonary artery smooth muscle cells (HPASMCs) in vitro; however, the mechanism by which to account for this effect is not known. We used systems biology to predict the protein NEDD9 as a critical node regulated by ALDO that controls fibrosis signaling in silico. To validate this finding, cells were treated with vehicle (V) control or ALDO (10-7 mol/L) for 24 hr. Compared to V-treated cells, ALDO increased NEDD9 significantly in HPAECs by 95% (P<0.05), but not in HPASMCs (P=NS) by immunoblot. However, NEDD9 was increased by 62% (P<0.05) in HPASMCs co-cultured with ALDO-treated HPAECs compared to ALDO-treated HPASMC monolayers. We hypothesized that ALDO induced cross-talk between cell types through a mechanism involving exosomes. To test this hypothesis, HPASMCs were incubated for 24 hr with exosomes from ALDO-treated HPAECs (ALDO-Exosome). Compared to V-treated cells, ALDO-Exosome increased NEDD9-positivity by 46% (P<0.001) and collagen III by 31% (P<0.001), by immunofluorescence and immunoblotting, respectively. Compared to control HPAECs, NEDD9 positivity was also increased in HPAECS from PAH patients by 170% (P<0.05), which correlated with collagen III levels (r=0.77, P<0.02). These data demonstrate that ALDO activates pro-fibrotic transcellular signaling between HPAECs-HPASMCs by a mechanism involving endothelial exosomes. Identifying NEDD9-collagen III signaling in the pathobiology of vascular fibrosis has important therapeutic implications for PAH patients.

About the author

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Andriy Samokhin

Postdoctoral fellow

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

United States

Key Contributors

Andriy O. Samokhin, George A. Alba, Bradley M. Wertheim, Elena Arons, Frederick P. Bowman, Jane A. Leopold, Bradley A. Maron Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

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