Endothelial SMAD4 Deficiency Promotes Pulmonary Hypertension by Impairing Cell Adhesion and Extracellular Matrix Organization

BACKGROUND: Aberrant BMPR2 (bone morphogenetic protein receptor 2) signaling is associated with the pathogenesis of pulmonary hypertension. SMAD4 (mothers against decapentaplegic homolog 4) is an essential downstream effector of BMPR2 signaling, but whether and how it participates in pulmonary hypertension are unclear. METHODS: Globally and vascular cell-specifically inducible knockout mouse models were used to examine the role of SMAD4 deficiency in differential cell compartments in the development of pulmonary hypertension. Single-cell transcriptomic analysis in combination with in vitro cell function measurements was conducted to provide mechanistic insights into pulmonary hypertension pathogenesis. RESULTS: loss on pulmonary hypertension. Finally, enhancing endothelial cell adhesion and ECM assembly by administrating an MMP (matrix metallopeptidase) inhibitor ilomastat could alleviate the pulmonary hypertension manifestations caused by endothelial SMAD4 deficiency. CONCLUSIONS: SMAD4 deficiency in endothelial cells, but not smooth muscle cells, plays a pathogenic role in pulmonary hypertension, via dampening endothelial cell-cell and cell-matrix adhesions and ECM organization.