Single-Cell Mapping of Large and Small Arteries During Hypertensive Aging

Vascular aging is directly related to several major diseases including clinical primary hypertension. Conversely, elevated blood pressure itself accelerates vascular senescence. However, the interaction between vascular aging and hypertension has not been characterized during hypertensive aging. To depict the interconnectedness of complex mechanisms between hypertension and aging, we performed single-cell RNA sequencing of aorta, femoral and mesentery arteries, respectively, from male Wistar Kyoto rats and male spontaneously hypertensive rats aging 16 or 72 weeks. We integrated 12 data sets to map the blood vessels of senile hypertension from 3 perspective: vascular aging, hypertension, and vascular type. We found that aging and hypertension independently exerted a significant impact on the alteration of cellular composition and artery remodeling, even greater when superimposed. Consistently, smooth muscle cells (SMCs) underwent phenotypic switching from contractile toward synthetic, apoptotic, and senescent SMCs with aging/hypertension. Furthermore, we identified 3 subclusters of Spp1high, encoding protein osteopontin (OPN), synthetic SMCs, Spp1high matrix activated fibroblasts, and Spp1high scar-associated macrophage involved in hypertensive aging. Spp1high scar-associated macrophage enriched for reactive oxygen species metabolic process and cell migration-associated function. Cell-cell communication analysis revealed Spp1-Cd44 receptor pairing was markedly aggravated in the hypertensive aging condition. Importantly, the concentration of serum OPN significantly potentiated in aged hypertensive patients compared with the normal group. Thus, we provide a comprehensive cell atlas to systematically resolve the cellular diversity and dynamic cellular communication changes of the vessel wall during hypertensive aging, identifying a protein marker OPN as a potential regulator of vascular remodeling during hypertensive aging.