Endothelial cell senescence exacerbates pulmonary hypertension by inducing juxtacrine Notch signaling in smooth muscle cells.

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure caused by pathological pulmonary artery remodeling. Here, we demonstrate that endothelial cell (EC) senescence plays a negative role in pulmonary hypertension via juxtacrine interaction with smooth muscle cells (SMCs). By using EC-specific progeroid mice, we discovered that EC progeria deteriorated vascular remodeling in the lungs, and exacerbated pulmonary hypertension in mice. Mechanistically, senescent ECs overexpressed Notch ligands, which resulted in increased Notch signaling and activated proliferation and migration capacities in neighboring SMCs. Pharmacological inhibition of Notch signaling reduced the effects of senescent ECs on SMCs functions in vitro, and improved the worsened pulmonary hypertension in EC-specific progeroid mice in vivo. Our findings show that EC senescence is a critical disease-modifying factor in PAH and that EC-mediated Notch signaling is a pharmacotherapeutic target for the treatment of PAH, particularly in the elderly.

Endothelin and the Cardiovascular System: The Long Journey and Where We Are Going.

Endothelin was first discovered more than 30 years ago as a potent vasoconstrictor. In subsequent years, three isoforms, two canonical receptors, and two converting enzymes were identified, and their basic functions were elucidated by numerous preclinical and clinical studies. Over the years, the endothelin system has been found to be critical in the pathogenesis of several cardiovascular diseases, including hypertension, pulmonary arterial hypertension, heart failure, and coronary artery disease. In this review, we summarize the current knowledge on endothelin and its role in cardiovascular diseases. Furthermore, we discuss how endothelin-targeting therapies, such as endothelin receptor antagonists, have been employed to treat cardiovascular diseases with varying degrees of success. Lastly, we provide a glimpse of what could be in store for endothelin-targeting treatment options for cardiovascular diseases in the future.

Endothelial Cell Senescence Exacerbates Pulmonary Fibrosis Potentially Through Accelerated Endothelial to Mesenchymal Transition.

Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease characterized by progressive lung fibrosis and obliteration of normal alveolar structures. Myofibroblasts play a central role in the progression of IPF by producing excess amount of extracellular matrix, and these myofibroblasts show heterogenous origins including resident fibroblasts, epithelial cells via epithelial to mesenchymal transition (EMT) and endothelial cell (EC) via endothelial to mesenchymal transition (EndMT). Although lung aging has been considered as essential mechanisms through abnormal activation of epithelial cells and fibroblasts, little is known about a role of EC senescence in the pathogenesis of IPF. Here, we reveal a detrimental role of EC senescence in IPF by utilizing unique EC-specific progeroid mice. EC-specific progeroid mice showed deteriorated pulmonary fibrosis in association with an accelerated EndMT in the lungs after intratracheal bleomycin instillation. We further confirmed that premature senescent ECs were susceptible to EndMT in vitro. Because senescent cells affect nearby cells through senescence-associated secretory phenotype (SASP), we assessed a potential role of the EC-SASP in EMT and myofibroblastic transition of resident fibroblasts. EC-SASP enhanced the myofibroblastic transition in resident fibroblasts, while no effect was detected on EMT. Our data revealed a previously unknown role of EC senescence in the progression of IPF, and thus rejuvenating ECs and/or inhibiting EC-SASP is an attracting therapeutic strategy for the treatment of IPF.