Pulmonary arterial hypertension is a progressive fatal disease that is characterized by pathological pulmonary artery remodeling, in which endothelial cell dysfunction is critically involved. We herein describe a previously unknown role of endothelial angiocrine in pulmonary hypertension. By searching for genes highly expressed in lung microvascular endothelial cells, we identify inhibin-β-A as an angiocrine factor produced by pulmonary capillaries. We find that excess production of inhibin-β-A by endothelial cells impairs the endothelial function in an autocrine manner by functioning as activin-A. Mechanistically, activin-A induces bone morphogenetic protein receptor type 2 internalization and targeting to lysosomes for degradation, resulting in the signal deficiency in endothelial cells. Of note, endothelial cells isolated from the lung of patients with idiopathic pulmonary arterial hypertension show higher inhibin-β-A expression and produce more activin-A compared to endothelial cells isolated from the lung of normal control subjects. When endothelial activin-A-bone morphogenetic protein receptor type 2 link is overdriven in mice, hypoxia-induced pulmonary hypertension was exacerbated, whereas conditional knockout of inhibin-β-A in endothelial cells prevents the progression of pulmonary hypertension. These data collectively indicate a critical role for the dysregulated endothelial activin-A-bone morphogenetic protein receptor type 2 link in the progression of pulmonary hypertension, and thus endothelial inhibin-β-A/activin-A might be a potential pharmacotherapeutic target for the treatment of pulmonary arterial hypertension.

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.

Pulmonary hypertension (PH) is a multi-etiological condition with a similar hemodynamic clinical sign and end result of right heart failure. Although its causes vary, a similar link across all the classifications is the presence of mitochondrial dysfunction. Mitochondria, as the powerhouse of the cells, hold a number of vital roles in maintaining normal cellular homeostasis, including the pulmonary vascular cells. As such, any disturbance in the normal functions of mitochondria could lead to major pathological consequences. The Warburg effect has been established as a major finding in PH conditions, but other mitochondria-related metabolic and oxidative stress factors have also been reported, making important contributions to the progression of pulmonary vascular remodeling that is commonly found in PH pathophysiology. In this review, we will discuss the role of the mitochondria in maintaining a normal vasculature, how it could be altered during pulmonary vascular remodeling, and the therapeutic options available that can treat its dysfunction.

Objective: Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfate N -acetylgalactosaminyltransferase-2), in macrophage foam cell formation. Approach and Results: ChGn-2-deficient mice showed decreased and shortened glycosaminoglycans. ChGn-2 ^−/− /LDLr ^−/− (low-density lipoprotein receptor) mice generated less atherosclerotic plaque after being fed with Western diet despite exhibiting a metabolic phenotype similar to that of the ChGn-2 ^+/+ /LDLr ^−/− littermates. We demonstrated that in macrophages, ChGn-2 expression was upregulated in the presence of oxLDL (oxidized LDL), and glycosaminoglycan was substantially increased. Foam cell formation was significantly altered by ChGn-2 in both mouse peritoneal macrophages and the RAW264.7 macrophage cell line. Mechanistically, ChGn-2 enhanced oxLDL binding on the cell surface, and as a consequence, CD36—an important macrophage membrane scavenger receptor—was differentially regulated. Conclusions: ChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic A graphic abstract is available for this article.

Advances in technology and biomedical knowledge have led to the effective diagnosis and treatment of an increasing number of rare diseases. Pulmonary arterial hypertension (PAH) is a rare disorder of the pulmonary vasculature that is associated with high mortality and morbidity rates. Although significant progress has been made in understanding PAH and its diagnosis and treatment, numerous unanswered questions remain regarding pulmonary vascular remodeling, a major factor contributing to the increase in pulmonary arterial pressure. Here, we discuss the role of activins and inhibins, both of which belong to the TGF-β superfamily, in PAH development. We examine how these relate to signaling pathways implicated in PAH pathogenesis. Furthermore, we discuss how activin/inhibin-targeting drugs, particularly sotatercep, affect pathophysiology, as these target the afore-mentioned specific pathway. We highlight activin/inhibin signaling as a critical mediator of PAH development that is to be targeted for therapeutic gain, potentially improving patient outcomes in the future.

Aging is accompanied by progressive vascular dysfunction, but its effects on skin aging remain poorly understood. Although endothelial cell (EC) senescence is implicated in various age-related diseases, its specific role in dermal aging remains unclear. Here we show that EC senescence contributes to intrinsic skin aging through immune dysregulation. Using an EC-specific senescent mouse model, we observe mast cell activation driven by the neuropeptide calcitonin gene-related peptide (CGRP), independent of traditional IgE-mediated pathways. Senescent ECs secreted pro-inflammatory senescence-associated secretory phenotype (SASP) factors, activating dermal neurons to produce CGRP, leading to mast cell degranulation and subsequent skin aging phenotypes. Pharmacological stabilization of mast cells or inhibition of the EC-SASP-CGRP pathway significantly attenuate dermal thinning, collagen degradation, and delayed wound healing, which are hallmarks of intrinsic skin aging. These findings identify vascular senescence as an upstream regulator of skin aging through a neuroimmune mechanism and suggest potential therapeutic targets for age-related skin deterioration.