Shabanian, T. | bioRxiv Science

bioRxiv2026

Gut Microbiota Production of Phenylacetate Programs Vascular Niche Senescence and Drives Atherosclerosis

Vascular senescence is a key contributor to ageing-related diseases, including atherosclerosis. Initial intervention is based on aggressive management of traditional risk factors, yet microbial metabolites remain underestimated as modifiable factors. We recently identified phenylacetate (PAA), a gut microbiota-linked metabolite, as a potent accelerator of endothelial senescence, raising the question of its causal role in atherosclerosis. Here, we show that PAA promotes vascular niche senescence and perivascular adipose tissue (PVAT) dysfunction, associated with atherosclerosis in humans and mice. Furthermore, PAA administration to atherosclerosis-prone mice was sufficient to drive atherosclerosis without altering lipid profile. Mechanistically, we found that PAA induces senescence-messaging secretome, containing IL-6, from endothelial cells, which stimulates Notch1 and disrupts insulin signaling in adipocytes. Blocking the PAA-IL-6-Notch1 axis as well as senolytics rescued adipocyte senescence and dysfunction. Identification of the strong link between PAA and atherosclerosis opens new avenues for microbiome-targeted preventive and therapeutic strategies in ageing. HighlightsO_LIAge-dependent increase in gut microbial metabolite PAA causally promotes vascular niche senescence C_LIO_LIPAA indirectly accelerates PVAT senescence through endothelial senescence-messaging secretome C_LIO_LISASP upregulates Notch1 signaling, leading to PVAT dysfunction C_LIO_LISenolytic therapy restores PVAT function C_LIO_LIPAA-induced vascular niche senescence contributes to atherosclerosis progression C_LI

cell biology↗

bioRxiv2024

AQP1 Differentially Orchestrates Endothelial Cell Senescence

Accumulation of senescent endothelial cells (ECs) with age is a pivotal driver of cardiovascular diseases in aging. However, little is known about the mechanisms and signaling pathways that regulate EC senescence. In this report, we delineate a previously unrecognized role of aquaporin 1 (AQP1) in orchestrating extracellular hydrogen peroxide (H2O2)-induced cellular senescence in aortic ECs. Our findings underscore AQP1s differential impact on senescence hallmarks, including cell-cycle arrest, senescence-associated secretory phenotype (SASP), and DNA damage responses, intricately regulating angiogenesis. In proliferating ECs, AQP1 is crucial for maintaining angiogenic capacity, whereas disruption of AQP1 induces morphological and mitochondrial alterations, culminating in senescence and impaired angiogenesis. Conversely, Aqp1 knockdown or selective blockade of AQP1 in senescent ECs rescues the excess H2O2-induced cellular senescence phenotype and metabolic dysfunction, thereby ameliorating intrinsic angiogenic incompetence. Mechanistically, AQP1 facilitates H2O2 transmembrane transport, exacerbating oxidant-sensitive kinases CaMKII-AMPK. This process suppresses HDAC4 translocation, consequently de-repressing Mef2A-eNOS signaling in proliferating ECs. However, in senescent ECs, AQP1 overexpression is linked to preserved HDAC4-Mef2A complex and downregulation of eNOS signaling. Together, our studies identify AQP1 as a novel epigenetic regulator of HDAC4-Mef2A-dependent EC senescence and angiogenic potential, highlighting its potential as a therapeutic target for antagonizing age-related cardiovascular diseases. Highlights* AQP1 is upregulated in aortic endothelial cells with aging * AQP1 differentially orchestrates H2O2-mediated EC senescence * AQP1 plays a dual role in regulating angiogenesis in proliferating and senescent ECs * AQP1 controls EC function by differentially modulating HDAC4-Mef2A pathway * AQP1 deficiency restores angiogenic capacity in senescent ECs

molecular biology↗