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Vascular EC-SOD limits the accumulation, proinflammatory profibrotic reprogramming, and hyaluronan binding of interstitial macrophages in hypoxia

ABSTRACT: Dysregulated redox signaling contributes to pulmonary hypertension (PH) and vascular-selective depletion of the redox enzyme EC-SOD (EC-SOD SMC KO) worsens chronic hypoxic PH. Given the important role of macrophages in vascular remodeling and PH, this study aimed to determine if interstitial macrophages (IMs) and their interactions with the extracellular matrix (ECM) component, hyaluronan, are modulated by vascular EC-SOD. Floxed wild-type (WT), EC-SOD SMC KO, and EC-SOD mimetic- or vehicle-treated mice were exposed to hypobaric hypoxia (~10% FiO2), for 4, 14, or 21 days. Using flow cytometry, we demonstrated that the transient increase in IMs at day 4 was exacerbated in EC-SOD SMC KO mice and prevented with EC-SOD mimetic (5 mg/kg, subcutaneous, day 1). Highlighting the importance of targeting vascular oxidative stress in the early response to hypoxia, pretreatment with this single dose of EC-SOD mimetic decreased right ventricular systolic pressure, right ventricular hypertrophy, and small vessel muscularization at day 21. To assess IM phenotypic reprogramming in this model, RNAseq was performed on flow-sorted IMs revealing baseline proinflammatory activation and enhanced activation of vascular and ECM remodeling pathways in response to hypoxia in EC-SOD SMC KO IMs compared to controls. To further investigate the ECM remodeling response, we quantified IMs expressing the hyaluronan receptor Lyve1, and IM-hyaluronan binding. Lyve1+IMs and Lyve1+HA+IMs were increased in response to hypoxia in EC-SOD SMC KO mice and accumulated in the perivascular space. In conclusion, vascular EC-SOD limits IM accumulation and proinflammatory profibrotic IM signaling, including perivascular accumulation of Lyve1+IMs and their binding to hyaluronan.

ORGANISM(S): Mus musculus

PROVIDER: GSE283567 | GEO | 2025/09/24

REPOSITORIES: GEO

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Project description:Intramuscular fat (IM; marbling) deposition is the deciding factor of beef quality grade in the U.S. Defining molecular mechanisms regulating adipogenesis in distinct anatomical areas in beef cattle is key to the development of strategies for marbling enhancement while limiting accumulation of excess subcutaneous adipose tissue (SAT; backfat). Our objective was to define the IM and SAT transcriptional heterogeneity at the whole tissue and single-cell levels in beef cattle. Longissimus dorsi muscle (9-11th rib) samples were collected from two harvested finished beef steers to dissect matched IM and adjacent SAT. Nuclei were isolated by dounce homogenization, then sequenced via bulk RNA sequencing (RNAseq) and single-nuclei RNA sequencing (snRNAseq) with 10x Genomics in an Illumina NovaSeq 6000. Analysis was conducted via Cell Ranger pipeline and Seurat in R Studio. By the expression of signature marker genes, snRNAseq analysis identified mature adipocytes (AD; ADIPOQ, LEP), adipose stromal and progenitor cells (ASPC; PDGFRA), endothelial cells (EC; VWF, PECAM1), smooth muscle cells (SMC; NOTCH3, MYL9) and immune cells (IMC; CD163, MRC1). We detected six cell clusters in SAT and nine in IM. Across IM and SAT, AD was the most abundant cell type, followed by ASPC, SMC, and IMC. In SAT, AD made up 50% of the cellular population, followed by ASPC (31%), EC (14%), IMC (1%), and SMC (4%). In IM depot, AD made up 23% of the cellular population, followed by ASPC with 19% of the population, EC with 28%, IMC with 7% and SMC with 12%. The abundance of ASPC and AD was lower in IM vs. SAT, while IMC was increased, suggesting a potential involvement of immune cells on IM deposition. Accordingly, both bulk RNAseq and snRNAseq analyses identified activated pathways of inflammation and metabolic function in IM. These results demonstrate distinct transcriptional cellular heterogeneity between SAT and IM depots in beef cattle, which may underly the mechanisms by which fat deposits in each depot. The identification of depot-specific cell populations in IM and SAT via snRNAseq analysis has the potential to reveal target genes for the modulation of fat deposition in beef cattle.

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Vascular EC-SOD limits the accumulation, proinflammatory profibrotic reprogramming, and hyaluronan binding of interstitial macrophages in hypoxia

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