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Carotid dysfunction in senescent female mice is mediated by increased α1A-adrenoceptor activity and COX-derived vasoconstrictor prostanoids
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Alpha-adrenergic receptors are crucial regulators of vascular hemodynamics and essential pharmacological targets for cardiovascular diseases. With aging, there is an increase in sympathetic activation, which could contribute to the progression of aging-associated cardiovascular dysfunction, including stroke. Nevertheless, there is little information directly associating adrenergic receptor dysfunction in the blood vessels of aged females. This study determined the role of a-adrenergic receptors in carotid dysfunction of senescent female mice (accelerated-senescence prone, SAMP8), compared to a non-senescent (accelerated-senescence prone, SAMR1). Vasoconstriction to phenylephrine (Phe) were markedly increased in common carotid artery of SAMP8 (AUC: 527±53) compared to SAMR1 (AUC: 334±30, p= 0.006). There were no changes in vascular responses to the vasoconstrictor agent U46619 or the vasodilators acetylcholine (ACh) and sodium nitroprusside (NPS). Hyperactivity to Phe in female SAMP8 was reduced by cyclooxygenase-1 and cyclooxygenase-2 inhibition and associated with augmented ratio of TXA2/PGI2 release (SAMR1: 1.1±0.1 vs. SAMP8: 2.1±0.3, p= 0.007). However, no changes in cyclooxygenase expression were seen in SAMP8 carotids. Selective a1A receptor antagonism markedly reduced maximal contraction, while a1D antagonism induced a minor shift in Phe contraction in SAMP8 carotids. Ligand binding analysis revealed a 3-fold increase of α-adrenergic receptor density in smooth muscle cells (VSMC) of SAMP8 versus SAMR1. Phe rapidly increased intracellular calcium (iCa+2) in VSMC via the a1A receptor, with a higher peak in VSMC from SAMP8,. In conclusion, senescence intensifies vasoconstriction mediated by a1A-adrenergic signaling in the carotid of female mice by mechanisms involving increased iCa+2 and release of cyclooxygenase-derived prostanoids.
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COSTA, Tiago j., BARROS, Paula r., DUARTE, Diego a., SILVA NETO, Julia a., HOTT, Sara cristina, SANTOS SILVA, Thamyris, COSTA NETO, Claudio m., GOMES, Felipe v., AKAMINE, Eliana h., MCCARTHY, Cameron g., JIMENEZ ALTAYO, Francesc, DANTAS, Ana paula, TOSTES, Rita c.. Carotid dysfunction in senescent female mice is mediated by increased α1A-adrenoceptor activity and COX-derived vasoconstrictor prostanoids. _American Journal Of Physiology-Heart And Circulatory Physiology_. 2023. Vol. 324, núm. 4, pàgs. 417-429. [consulta: 25 de febrer de 2026]. ISSN: 1522-1539. [Disponible a: https://hdl.handle.net/2445/206267]