Pulmonary hypertension (PH) is marked by dysfunction of pulmonary arterial endothelial cells (PAEC), which further drives vascular remodeling. In PH secondary to left heart disease (PH-LHD), the mechanisms of PAEC maladaptation are so far not understood.
In primary PAEC from PH-LHD patients, increased proliferation and migration were associated with impaired bone morphogenetic protein (BMP) signaling as evidenced by reduced BMPR2 expression, decreased SMAD1/5/8 phosphorylation, and a diminished response to BMP2. Transcriptomic and proteomic analyses also revealed abundant expression of the secreted ligand growth differentiation factor 6 (GDF6) and the BMP antagonist gremlin-1 (GREM1) across lung vascular cells in PH-LHD patients and a corresponding rat model.
Exogenous GDF6 activated BMP, TGF-β, and ERK1 pathways in healthy PAEC, yet in PH-LHD PAEC, BMP signaling was reduced, while pro-proliferative TGF-β and ERK1 pathways were hyperactivated. Mechanistically, GDF6 activated ERK1 via VEGFR2, leading to increased TGF-β expression and SMAD3 activation through TGFBR1, which in turn upregulated GREM1. Functionally, GDF6 promoted proliferation and migration in healthy PAEC, and GDF6 knockdown normalized these functions in PH-LHD PAEC. In a preclinical rat model, GDF6 knockdown reduced pulmonary vascular remodeling and alleviated PH.
This study identifies elevated GDF6 and increased signaling via the VEGFR2/ERK1, subsequent activation of TGF-β/TGFBR1 signaling and inhibition of BMP signaling via GREM1 as key drivers of endothelial dysfunction and vascular remodeling in PH-LHD.
Acknowledgments: Supported by the German Center for Cardiovascular Research (DZHK), the Federal Ministry of Education and Research (BMBF), the Sonnenfeld Foundation, the German Research Foundation (DFG; Project ID: 549161294), and the Collaborative Research Center 1470 (Project ID: 437531118, Sub-project A04).
