| Autor: |
J D Symons, Denise J. Morgan, Sihem Boudina, Amber D. Bledsoe, Tandar M, Jae Min Cho, Satya P. Kunapuli, Tianxin Yang, Sohom Mookherjee, Kishore Bk, Joel D. Trinity, Fei Wang, Russell S. Richardson, James Cerbie, Seul-Ki Park, Oh Sung Kwon, Anandh Babu Pv, Ashely Nelson, Leena P. Bharath, Fermoyle Cc |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
ObjectiveThe importance of endothelial cell (EC) autophagy to vascular homeostasis is evolving. Earlier we reported that purinergic 2Y1 receptor (P2Y1-R) activation rejuvenates shearstress induced nitric oxide (NO) generation in bovine aortic endothelial cells that is otherwise compromised after pharmacological and genetic autophagy repression. Here we determined the translational and functional relevance of these findings.Approach and ResultsFirst we assessed translational relevance using older humans and mice that exhibit blunted EC autophagy at rest together with impaired arterial function vs. appropriate controls. Rhythmic handgrip exercise elevated radial artery shear rate similarly in adult and older males for 60-min. Compared to baseline, autophagy initiation, p-eNOSS1177 activation, and NO generation, occurred in radial artery ECs from adult but not older subjects. Regarding mice, indexes of autophagy and p-eNOSS1177 activation were robust in ECs from adult but not older mice in response to 60-min treadmill-running. Next we questioned whether an inability to initiate EC autophagy precipitates arterial dysfunction. Age-associated reductions in intraluminal flow-mediated vasodilation observed in older vs. adult mice were recapitulated in arteries from adult mice by : (i) NO synthase inhibition; (ii) autophagy impairment using 3-methyladenine (3-MA); (iii) EC Atg3 depletion (iecAtg3KO mice); (iv) P2Y1-R blockade; and (v) germline depletion of P2Y1-Rs. Importantly, P2Y1-R activation using 2-methylthio-ADP (2-Me-ADP) improved vasodilatory capacity in arteries from : (i) adult mice treated with 3-MA; (ii) adult iecAtg3KO mice; and (iii) older animals with repressed EC autophagy.ConclusionsArterial dysfunction concurrent with pharmacological, genetic, and age-associated EC autophagy compromise is improved by activating P2Y1-Rs. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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