Mapping the unicellular transcriptome of the ascending thoracic aorta to changes in mechanosensing and mechanoadaptation during aging

Abstract

Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano-molecular programs that orchestrate region- and layer-specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic (ATA) compared to distal segments of the aorta and that tissues in both the medial and adventitial compartments of the ATA stiffen during aging. Single-cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T-lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T-lymphocytes accumulate in the adventitia and likely promote fibrosis, while activation of mechanosensitive piezo-1 enhances medial vasoconstriction. These results portray the immuno-mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi-gerogenic signals priming to disease development.

The Fbn1 gene variant governs passive ascending aortic mechanics in the mgΔlpn mouse model of Marfan syndrome when superimposed to perlecan haploinsufficiency

“…5 ). These estimates are in close agreement with experimental ( 33 , 39 , 40 ) and theoretical ( 38 ) values from literature. All 12-week-old Hspg2 specimens fell within the 95% confidence interval for the expected ATA diameter by body mass ( Figure 1G ).…”

“…All biomechanical testing and data analysis was performed consistent with established methods ( 12 , 32 , 33 , 34 ). The thoracic aorta was cleaned of excess fat and perivascular tissues, while preserving lateral branches.…”

“…The coefficients and were determined by linear regression on predicted luminal diameters at systole for female C57BL/6 WT mice in this study pooled with prior data by our group ( 33 ). Vessels that fell beyond the 95% confidence interval for normal allometric scaling were classified as dilated.…”

Chronic Pod-Mod E-Cigarette Aerosol Exposure Induces Aortic Dysfunction in Hypercholesterolemic Mice: Role of Oxidative Stress and Inflammation

“…Whole aortas were immediately excised, immersed in chilled (4 ◦ C) Hank’s buffered salt solution (HBSS), and prepared for mechanical testing as previously described. 31, 34 Briefly, the ascending thoracic aorta (ATA) was sectioned between the aortic root and the brachiocephalic artery, while the suprarenal abdominal aorta (SAA) was segmented from the diaphragm to the right renal artery. Aortic samples were cleaned of perivascular tissue to facilitate ligation of lateral branches using a single strand of a braided 9-0 suture.…”

The Role of Cdc42 in the Insulin and Leptin Pathways Contributing to the Development of Age-Related Obesity

“…The activation of Cdc42 by protein kinase C delta type initiates the production of type I collagen from vascular smooth muscle cells [221]. Aging increases Cdc42 signaling in VSMC [223], potentially increasing collagen I secretion and leading to vascular fibrosis and atherosclerosis complications [224]. Moreover, overexpression of Cdc42 may increase arterial stiffness due to enhanced osteogenic differentiation of VSMC and subsequent vascular calcification [225].…”