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Intraflagellar transport protein 88 (Ift88) is required for ciliogenesis and shear stress-induced dissolution of cilia in embryonic endothelial cells coincides with endothelial-to-mesenchymal transition (EndMT) in the developing heart. EndMT is also suggested to underlie heart and lung fibrosis, however, the mechanism linking endothelial Ift88, its effect on EndMT and organ fibrosis remains mainly unexplored. We silenced  Ift88  in endothelial cells (ECs)  in vitro  and generated endothelial cell-specific Ift88-knockout mice (Ift88 endo )  in vivo  to evaluate EndMT and its contribution towards organ fibrosis, respectively.  Ift88- silencing in ECs led to mesenchymal cells-like changes in endothelial cells. The expression level of the endothelial markers (CD31, Tie-2 and VE-cadherin) were significantly reduced with a concomitant increase in the expression level of mesenchymal markers (αSMA, N-Cadherin and FSP-1) in  Ift88 -silenced ECs. Increased EndMT was associated with increased expression of profibrotic  Collagen I  expression and increased proliferation in  Ift88 -silenced ECs. Loss of Ift88 in ECs was further associated with increased expression of Sonic Hedgehog signaling effectors.  In vivo , endothelial cells isolated from the heart and lung of Ift88 endo  mice demonstrated loss of Ift88 expression in the endothelium. The Ift88 endo  mice were born in expected Mendelian ratios without any adverse cardiac phenotypes at baseline. Cardiac and pulmonary endothelial cells isolated from the Ift88 endo  mice demonstrated signs of EndMT and bleomycin treatment exacerbated pulmonary fibrosis in Ift88 endo  mice. Pressure overload stress in the form of aortic banding did not reveal a significant difference in cardiac fibrosis between Ift88 endo  mice and control mice. Our findings demonstrate a novel association between endothelial cilia with EndMT and cell proliferation and also show that loss of endothelial cilia-associated increase in EndMT contributes specifically towards pulmonary fibrosis.

Endothelial-specific Loss of IFT88 Promotes Endothelial-to-Mesenchymal Transition and Exacerbates Bleomycin-induced Pulmonary Fibrosis