Pericytes contribute to pulmonary vascular remodeling via HIF2α signaling

Abstract

Vascular remodeling is the process of structural alteration and cell rearrangement of blood vessels in response to injury and is the cause of many of the world’s most afflicted cardiovascular conditions, including pulmonary arterial hypertension (PAH). Many studies have focused on the effects of vascular endothelial cells and smooth muscle cells (SMCs) during vascular remodeling, but pericytes, an indispensable cell population residing largely in capillaries, are ignored in this maladaptive process. Here, we report that hypoxia-inducible factor 2α (HIF2α) expression is increased in the lung tissues of PAH patients, and HIF2α overexpressed pericytes result in greater contractility and an impaired endothelial-pericyte interaction. Using single-cell RNAseq and hypoxia-induced pulmonary hypertension (PH) models, we show that HIF2α is a major molecular regulator for the transformation of pericytes into SMC-like cells. Pericyte-selective HIF2α overexpression in mice exacerbates PH and right ventricular hypertrophy. Temporal cellular lineage tracing shows that HIF2α overexpressing reporter NG2+ cells (pericyte-selective) relocate from capillaries to arterioles and co-express SMA. This novel insight into the crucial role of NG2+ pericytes in pulmonary vascular remodeling via HIF2α signaling suggests a potential drug target for PH.

Specialized Pericyte Subtypes in the Pulmonary Capillary

“…Differentially expressed genes (DEG) to compare IPAH Type 2 PCs with healthy Type 2 PCs only revealed two significantly altered genes (adjusted P<0.02 ), which are VIM ( Fig 5D ) and ITM2C . IPAH Type 1 PCs compared to healthy Type 1 PCs also only show two significantly altered genes (adjusted P<0.02 ), which are MT2A and MT1M , When re-analyzed hypoxic murine mural cells scRNAseq datasets from our recent published work 31 , we identified PC clusters from other mural populations using high expression levels of Higd1b ( Fig 5E ). Due to limited cell numbers, we can not further sub-cluster the murine PC population.…”

“…Next, we re-analyzed idiopathic pulmonary arterial hypertension (IPAH) PCs and control PCs utilizing previously published scRNAseq data sets and analysis methods. 31,32 Among the sub-reclustered 13 mural cell clusters, only sub-Clusters 5 and 6 had expressions of HIGD1B ( Fig 5C, left ). Voline plots show that sub-Cluster 5 is HIGD1B low PDGFRB high as defined as Type 2 PCs whereas sub-Cluster 6 is HIGD1B high PDGFRB low as defined as Type 1 PCs.…”

“…For connective tissue preparation, the tissue surrounding the descending aorta in the abdominal cavity was identified and dissected after the removal of the mediastinal contents as previously described. 31 Connective tissue and skeletal muscle were placed in 4% PFA at 4°C overnight and then washed in 1X PBS for another day.…”

Increased HIF-2α activity in the nucleus pulposus causes intervertebral disc degeneration in the aging mouse spine

“…These results suggested that perturbations of cell metabolism and circadian clock may partially underscore matrix changes and degeneration in K19-HIF-2dPA mice. Of interest, there was a recent study highlighting contribution of elevated HIF-2α levels to increased contractility and pathological transformation of pericytes into vascular smooth muscle-like cells in pulmonary arterial hypertension, and its activation aids in vascular remodeling (Kim et al, 2024). Schematic summarizing the consequences of elevated HIF-2α levels in the NP compartment on intervertebral disc health with spine aging.…”

Signaling Role of Pericytes in Vascular Health and Tissue Homeostasis

“…Similarly, HIF-2α has played a significant role in pulmonary vascular remodeling in conditions such as pulmonary arterial hypertension (PAH), affecting pericyte–endothelial cell interactions and enhancing vessel contractility. Indeed, the overexpression of HIF-2α has been associated with a greater contractility and impaired endothelial cells-pericytes interaction [ 67 ].…”