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 have 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 (WKY) and male spontaneously hypertensive rats (SHR) aging 16 or 72 weeks. We integrated 12 datasets to map the blood vessels of senile hypertension from three 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 towards synthetic, apoptotic and senescent SMCs with aging/hypertension. Furthermore, we identified three sub-clusters of Spp1  high, encoding protein osteopontin (OPN), synthetic SMCs, Spp1  high matrix-activated fibroblasts and Spp1  high scar-associated macrophage involved in hypertensive aging. Spp1  high 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 on hypertensive aging condition. Importantly, the concentration of serum OPN significantly potentiated in aged hypertensive patients compared with 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.