Endothelial‐dependent Activation of Smooth Muscle PDGF Receptors Enhances PASMC Proliferation in IPAH

Platelet‐derived growth factor (PDGF), is one of the major growth factors found in mammalian serum, which plays an important role in cell growth. It has been previously demonstrated that abnormal activation of the PDGF signaling pathway can contribute to aberrant pulmonary vascular remodeling and pulmonary hypertension via active PDGF receptors. The overall goal of this study was to examine the expression of the PDGFR isoforms in both pulmonary artery smooth muscle cells (PASMC) and pulmonary artery endothelial cells (PAEC) and to identify whether PDGF produced in PASMC or PAEC promotes PASMC cell proliferation. We observed that the protein and mRNA expression level of both PDGFRα and PDGFRβ were upregulated in IPAH patients in comparison to normal PASMC. However, expression of PDGFRα and PDGFRβ was not detected in PAEC. PDGF treatment enhanced the activity of PDGFRα and PDGFRβ, as determined by phosphorylation of PDGFRα and PDGFRβ in IPAH PASMC compared to control. Furthermore, the PDGF‐induced rise in cytosolic free Ca2+ was also increased in IPAH PASMC in comparison to normal PASMC. Treatment with normal PAEC cultured conditioned medium enhanced PDGFRα activation in IPAH PASMC than normal PASMC, while normal PASMC cultured conditioned medium had no effect on p‐PDGFRα and p‐PDGFRβ. We further found that the expression level of PDGFA and PDGFB were increased in IPAH PAEC compare to normal PAEC. Additionally, the expression level of PDGFA and PDGFB in PAEC were increased in normoxic condition compare to hypoxia. Normal PAEC cultured conditioned medium promotes cell proliferation in PASMC; proliferation was markedly higher in IPAH PAEC cultured conditioned medium, but not in PASMC cultured conditioned medium. The data showed that the expression and activity of PDGF receptor were increased in IPAH PASMC. Overall these results suggest that IPAH PAEC secret high‐levels of PDGF to the PASMC, which can affect active PDGF receptor, promoting PASMC proliferation which can lead to pulmonary hypertension.Support or Funding InformationThis study was supported in part by the grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL135807 and HL125208), the National Natural Science Foundation of China (81630004, 81470246, 81220108001 and 81520108001), the Guangzhou Department of Education Yangcheng Scholarship (12A001S), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme of China, China Scholarship Council (201608440324) and the Actelion ENTELLIGENCE Young Investigator Award.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.