Hypoxia-Induced Metabolic Reprogramming and Markings of Cell Fate in Concentric Arterial Hypertrophy

Ferreira de Almeida, L.; Smith, J. P.; Yamaguchi, M.; Medrano, S.; Martini, A.; Matsuoka, D.; Juskiewicz, Z. J.; Isakson, B. E.; Yamaguchi, H.; Trevisan-Silva, D.; Wagamon, T.; Sequeira-Lopez, M. L. S.; Gomez, R. A.

doi:10.1101/2025.07.09.663881

bioRxiv · 10.1101/2025.07.09.663881

Hypoxia-Induced Metabolic Reprogramming and Markings of Cell Fate in Concentric Arterial Hypertrophy

Ferreira de Almeida, L.·Smith, J. P.·Yamaguchi, M.·Medrano, S.·Martini, A.·Matsuoka, D.·Juskiewicz, Z. J.·Isakson, B. E.·Yamaguchi, H.·Trevisan-Silva, D.·Wagamon, T.·Sequeira-Lopez, M. L. S.·Gomez, R. A.

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Abstract

Chronic inhibition of the renin-angiotensin system (RAS), while widely used to treat hypertension, can lead to an underrecognized form of vascular disease marked by concentric arteriolar and arterial hypertrophy (CAAH). Here, using two lineage-traced mouse models of genetic renin deletion and sustained RAS blockade, we uncover a pathogenic cascade initiated by renin-lineage cell fate reprogramming. Loss of endocrine identity and transformation of smooth muscle cells drives a shift toward a fibrotic, inflammatory, and secretory phenotype that remodels the extracellular matrix and promotes vascular thickening and luminal narrowing. Integrated transcriptomic, proteomic, and metabolomic profiling revealed a hypoxia-linked metabolic switch--characterized by succinate accumulation and NAD+ depletion--coupled to Hif activation and disease progression. We identify Cdh13 and collagens (including Col1a1 and Col12a1) as early urinary biomarkers and define a 10-gene molecular signature of CAAH with potential clinical application. These findings establish renin-lineage cell plasticity and metabolic dysfunction as central drivers of CAAH and nominate candidate biomarkers for early detection and therapeutic targeting in RAS-inhibited patients.

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Ferreira de Almeida, L., Smith, J. P., Yamaguchi, M., Medrano, S., Martini, A., Matsuoka, D., Juskiewicz, Z. J., Isakson, B. E., Yamaguchi, H., Trevisan-Silva, D., Wagamon, T., Sequeira-Lopez, M. L. S., Gomez, R. A.. 2025-07-14. Hypoxia-Induced Metabolic Reprogramming and Markings of Cell Fate in Concentric Arterial Hypertrophy. https://doi.org/10.1101/2025.07.09.663881

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