Age-related differences in the cutaneous vascular response to exogenous angiotensin II

Abstract

Angiotensin II (ANG II) is locally produced in human skin and contributes to the reflex vasoconstriction (VC) response in aged but not young skin. We hypothesized that the exogenous ANG II-mediated VC response would be greater in older adults and would be affected by inhibition of adrenoreceptor or ANG II type II receptor (AT2R) pathways. Three microdialysis (MD) fibers were placed in the forearm skin of 11 young (26 ± 3 yr) and 11 older (68 ± 4 yr) individuals for perfusion of 1) Ringer solution (control), 2) adrenoreceptor blockade with yohimbine + propranolol, and 3) AT2R inhibition with PD-123319. ANG II was then added to the perfusates at eight graded dose concentrations ranging from 10−10 to 10−3 M. Laser Doppler flux was measured at each MD site, and cutaneous vascular conductance (CVC) was calculated as CVC = laser Doppler flux/mean arterial pressure and normalized to baseline CVC values collected before ANG II perfusion (%ΔCVCbaseline). At the control site, older adults (−34 ± 4%ΔCVCbaseline) exhibited a greater peak VC compared with young adults (−22 ± 2%ΔCVCbaseline, P < 0.05), which was attenuated with adrenoreceptor blockade. Young skin exhibited a vasodilation in response to lower ANG II doses that was inhibited with AT2R inhibition. AT2R inhibition also increased the VC response to higher ANG II doses such that young skin responded similarly to older skin. These results indicate that ANG II has a greater VC influence in older than young individuals. Furthermore, ANG II may be affecting multiple targets, including adrenergic and AT2R pathways. NEW & NOTEWORTHY Intradermal perfusion of successive doses of angiotensin II (ANG II) revealed a role for ANG II type II receptors and dose-dependent, ANG II-mediated vasodilation in young but not older adults. In contrast, older adults exhibited greater vasoconstriction for a given dose of ANG II. The increased vasoconstriction in older adults was subsequently blunted with adrenoreceptor blockade, which indicates an interaction between ANG II and adrenergic signaling pathways in the cutaneous microcirculation.

Pernio (Chilblains), SARS-CoV-2, and COVID Toes Unified Through Cutaneous and Systemic Mechanisms

“…135 The result in older adults is increased reliance on ANGIImediated vasoconstriction through AT1R stimulation of the compromised sympathetic pathways. 77 The age-related differences in ANGII response also suggest that as adults age, AT1R density increases whereas AT2R density decreases, and the dose-response curve shifts in older adults, with less AT2R-mediated vasodilation (which is protective) at lower ANGII concentrations and more AT1R-mediated vasoconstriction (which is pathogenic) with increasing ANGII concentrations. 77 Nevertheless, younger adults do have AT1R-mediated vasoconstriction at higher levels of ANGII, but, unlike older individuals, younger adults maintain adequate reflex cutaneous vasoconstriction to cold exposure.…”

“…77 The age-related differences in ANGII response also suggest that as adults age, AT1R density increases whereas AT2R density decreases, and the dose-response curve shifts in older adults, with less AT2R-mediated vasodilation (which is protective) at lower ANGII concentrations and more AT1R-mediated vasoconstriction (which is pathogenic) with increasing ANGII concentrations. 77 Nevertheless, younger adults do have AT1R-mediated vasoconstriction at higher levels of ANGII, but, unlike older individuals, younger adults maintain adequate reflex cutaneous vasoconstriction to cold exposure. 77,133 Therefore, locally increased ANGII due to ACE2 deficiency from SARS-CoV-2 infection, in combination with an intact thermoregulatory vasoconstriction response, may contribute to the acral vasopasm of pernio more commonly affecting younger patients with COVID-19.…”

“…Severe COVID-19 occurs more frequently in male patients 73,74 and older patients. 75 Differences in the RAAS may be one explanation, as in male patients and older adults the angiotensin-converting enzymeedriven ANGII-AT1R axis is favored, 76,77 whereas in female patients the balance is shifted toward increased activity of ACE2 and the positive effects of ANG1-7 binding AT2R and the Mas receptor. 76 Estradiol increases ANG1-7 production through estrogen receptor a and increases ACE2 expression and activity.…”

“…132 Cutaneous vascular responses to ANGII are age-related. 77,133 In young adults, reflex cutaneous vasoconstriction to cold exposure is primarily dependent on sympathetic nerve activity. 134 However, thermoregulatory reflex cutaneous vasoconstriction attenuates with older age because of impaired skin sympathetic nerve activity.…”

“…77 Nevertheless, younger adults do have AT1R-mediated vasoconstriction at higher levels of ANGII, but, unlike older individuals, younger adults maintain adequate reflex cutaneous vasoconstriction to cold exposure. 77,133 Therefore, locally increased ANGII due to ACE2 deficiency from SARS-CoV-2 infection, in combination with an intact thermoregulatory vasoconstriction response, may contribute to the acral vasopasm of pernio more commonly affecting younger patients with COVID-19.…”