Carotid dysfunction in senescent female mice is mediated by increased α 1A -adrenoceptor activity and COX-derived vasoconstrictor prostanoids

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 324; no. 4; pp. H417 - H429
• Main Authors: Costa, Tiago J, Barros, Paula R, Duarte, Diego A, Silva-Neto, Júlio A, Hott, Sara Cristina, Santos-Silva, Thamyris, Costa-Neto, Claudio M, Gomes, Felipe V, Akamine, Eliana H, McCarthy, Cameron G, Jimenez-Altayó, Francesc, Dantas, Ana Paula, Tostes, Rita C
• Format: Journal Article
• Language: English
• Published: United States 01.04.2023
• Subjects: Aged; Aging - metabolism; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Female; Humans; Male; Mice; Phenylephrine - pharmacology; Prostaglandins - metabolism; Vasoconstrictor Agents - pharmacology; common carotid; cerebrovascular function; α-adrenergic receptor; senescence-accelerated mice; menopause
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00495.2022

α-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 with a nonsenescent (accelerated-senescence prone, SAMR1). Vasoconstriction to phenylephrine (Phe) was markedly increased in common carotid artery of SAMP8 [area under the curve (AUC), 527 ± 53] compared with SAMR1 (AUC, 334 ± 30, = 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, = 0.007). However, no changes in cyclooxygenase expression were seen in SAMP8 carotids. Selective α -receptor antagonism markedly reduced maximal contraction, whereas α antagonism induced a minor shift in Phe contraction in SAMP8 carotids. Ligand binding analysis revealed a threefold increase of α-adrenergic receptor density in smooth muscle cells (VSMCs) of SAMP8 vs. SAMR1. Phe rapidly increased intracellular calcium (Ca ) in VSMCs via the α -receptor, with a higher peak in VSMCs from SAMP8. In conclusion, senescence intensifies vasoconstriction mediated by α -adrenergic signaling in the carotid of female mice by mechanisms involving increased Ca and release of cyclooxygenase-derived prostanoids. The present study provides evidence that senescence induces hyperreactivity of α -adrenoceptor-mediated contraction of the common carotid. Impairment of α -adrenoceptor responses is linked to increased Ca influx and release of COX-derived vasoconstrictor prostanoids, contributing to carotid dysfunction in the murine model of female senescence (SAMP8). Increased reactivity of the common carotid artery during senescence may lead to morphological and functional changes in arteries of the cerebral microcirculation and contribute to cognitive decline in females. Because the elderly population is growing, elucidating the mechanisms of aging- and sex-associated vascular dysfunction is critical to better direct pharmacological and lifestyle interventions to prevent cardiovascular risk in both sexes.