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

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Cell Biology

Background:

• Aberrant bone morphogenetic protein receptor 2 (BMPR2) signaling is implicated in pulmonary hypertension pathogenesis.
• SMAD4, a key downstream effector of BMPR2, has an unclear role in this disease.

Purpose of the Study:

• To investigate the role of SMAD4 deficiency in different vascular cell types in the development of pulmonary hypertension.
• To elucidate the cellular and molecular mechanisms underlying SMAD4's function in pulmonary hypertension.

Main Methods:

• Generated inducible knockout mouse models with global and cell-specific SMAD4 deletion (endothelial and smooth muscle cells).
• Utilized single-cell transcriptomic analysis and in vitro cell function assays.
• Examined pulmonary hypertension manifestations, cardiovascular abnormalities, and extracellular matrix (ECM) organization.

Main Results:

• Endothelial cell-specific SMAD4 deletion induced pulmonary hypertension, characterized by elevated right ventricle systolic pressure and distal pulmonary vessel muscularization.
• Smooth muscle cell-specific SMAD4 deletion led to aortic aneurysm and dissection, not pulmonary hypertension.
• SMAD4 deficiency in endothelial cells impaired cell-cell and cell-matrix adhesions, disorganized ECM, and increased vascular leak.
• Endothelial Itgb1 deletion mimicked endothelial SMAD4 loss effects; MMP inhibitor ilomastat ameliorated pulmonary hypertension.

Conclusions:

• SMAD4 deficiency in endothelial cells, not smooth muscle cells, is pathogenic in pulmonary hypertension.
• This pathogenic role is mediated by impaired endothelial cell adhesion and ECM organization.
• Targeting endothelial cell adhesion pathways may offer therapeutic potential for pulmonary hypertension.