PHD2 deletion in endothelial or arterial smooth muscle cells reveals vascular cell type-specific responses in pulmonary hypertension and fibrosis

Abstract

Hypoxia plays an important regulatory role in the vasculature to adjust blood flow to meet metabolic requirements. At the level of gene transcription, the responses are mediated by hypoxia-inducible factor (HIF) the stability of which is controlled by the HIF prolyl 4-hydroxylase-2 (PHD2). In the lungs hypoxia results in vasoconstriction, however, the pathophysiological relevance of PHD2 in the major arterial cell types; endothelial cells (ECs) and arterial smooth muscle cells (aSMCs) in the adult vasculature is incompletely characterized. Here, we investigated PHD2-dependent vascular homeostasis utilizing inducible deletions of PHD2 either in ECs (Phd2∆ECi) or in aSMCs (Phd2∆aSMC). Cardiovascular function and lung pathologies were studied using echocardiography, Doppler ultrasonography, intraventricular pressure measurement, histological, ultrastructural, and transcriptional methods. Cell intrinsic responses were investigated in hypoxia and in conditions mimicking hypertension-induced hemodynamic stress. Phd2∆ECi resulted in progressive pulmonary disease characterized by a thickened respiratory basement membrane (BM), alveolar fibrosis, increased pulmonary artery pressure, and adaptive hypertrophy of the right ventricle (RV). A low oxygen environment resulted in alterations in cultured ECs similar to those in Phd2∆ECi mice, involving BM components and vascular tone regulators favoring the contraction of SMCs. In contrast, Phd2∆aSMC resulted in elevated RV pressure without alterations in vascular tone regulators. Mechanistically, PHD2 inhibition in aSMCs involved actin polymerization -related tension development via activated cofilin. The results also indicated that hemodynamic stress, rather than PHD2-dependent hypoxia response alone, potentiates structural remodeling of the extracellular matrix in the pulmonary microvasculature and respiratory failure.

Cooperation of Angiopoietin-2 and Angiopoietin-4 in Schlemm's Canal Maintenance

“…To characterize the potential role of Angpt4 in the AH drainage and SC, we first investigated its expression in the iridocorneal angle. By crossing the genetic cell fate mapping mouse line Rosa26 mTmG with Angpt4 Cre mice, 23 , 38 we were able to visualize the cells that express or have expressed Cre recombinase under the Angpt4 promoter by Cre-mediated conversion of continuous tdTomato expression to membrane-targeted green fluorescence protein (GFP) expression. We observed that the Angpt4 -driven GFP signal started postnatally: at P5 (postnatal day 5) and P10, flat-mounted corneal limbus samples had only very few, faint GFP + cells, while at P13, their number and signal intensity were beginning to multiply ( Fig.…”

“…Angpt4 Cre/+ ; Rosa26 mTmG/+ cell fate mapping and Angpt4 LacZ reporter mice have been introduced before. 23 , 38 …”

Silencing of NOTCH3 Signaling in Meniscus Smooth Muscle Cells Inhibits Fibrosis and Exacerbates Degeneration in a HEYL‐Dependent Manner

“…For instance, the aberrant proliferation of smooth muscle cells increased periarterial fibrosis and consequently promoted pulmonary hypertension. [ 29 , 30 ] Smooth muscle cells repression relieved pulmonary hypertension through fibrosis inhibition. [ 31 ] In a meniscus injury model, smooth muscle cells proliferated and migrated to the injury site to promote repair.…”

The mapping of mRNA alterations elucidates the etiology of radiation-induced pulmonary fibrosis

“…The associated significantly dysregulated genes included IGHV1-58, CWH43, IGHV1-54, IGKV4-63, IGHV1-75, and IGKV1-135 . Imbalanced angiogenesis and abnormal blood vessel function is a common pathological process in respiratory disorders, including idiopathic pulmonary fibrosis, pulmonary arterial hypertension, chronic obstructive pulmonary disease, hepatopulmonary syndrome, and cigarette associated lung injury ( Hanumegowda et al, 2012 ; Raevens et al, 2018 ; Eldridge and Wagner, 2019 ; Yang et al, 2021 ; Elamaa et al, 2022 ). Angiogenesis was also observed during the early to middle stages of RIPF.…”