Carotid dysfunction in senescent female mice is mediated by increased a1A-adrenoceptor activity and COX-derived vasoconstrictor prostanoids

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Costa, Tiago J. ; Barros, Paula R. ; Duarte, Diego A. ; Silva-Neto, Julio A. ; Hott, Sara Cristina ; Santos-Silva, Thamyris ; Costa-Neto, Claudio M. ; V. Gomes, Felipe ; Akamine, Eliana H. ; McCarthy, Cameron G. ; Jimenez-Altayo, Francesc ; Dantas, Ana Paula ; Tostes, Rita C.

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY; v. 324, n. 4, p. 13-pg., 2023-04-01.

Abstract

a-Adrenergic receptors are crucial regulators of vascular hemodynamics and essential pharmacological targets for cardiovascular dis-eases. With aging, there is an increase in sympathetic activation, which could contribute to the progression of aging-associated cardi-ovascular 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, 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, whereas a1D antagonism induced a minor shift in Phe contraction in SAMP8 carotids. Ligand binding analysis revealed a threefold increase of a-adrenergic receptor density in smooth muscle cells (VSMCs) of SAMP8 vs. SAMR1. Phe rapidly increased intracellular calcium (Cai2+) in VSMCs via the a1A-receptor, with a higher peak in VSMCs from SAMP8. In conclusion, senescence intensifies vasoconstriction mediated by a1A-adrenergic signaling in the carotid of female mice by mechanisms involving increased Cai2+ and release of cyclooxygenase-derived prostanoids. (AU)

• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 17/25116-2 - Role of O-GlcNacylation (O-GlcNAc) on the expression and function of classical estrogen receptor alpha (ERa66kDa) and splice variant of estrogen receptor alpha (ERa36kDa) in the common carotid artery of aging mice
• Grantee: Tiago Januário da Costa
• Support Opportunities: Scholarships in Brazil - Post-Doctoral