Global Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric Hypoxia

Abstract

Rationale: Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from excessive erythrocytosis (EE); however, the mechanistic link between chronically elevated sympathetic nervous activity and hypoxia-induced vascular dysfunction has not been determined. Objective: To determine the impact of heightened sympathetic nervous activity on resistance artery endothelial-dependent dilation (EDD), and endothelial-independent dilation, in lowlanders and Andean highlanders with and without EE. Methods and Results: We tested healthy lowlanders (n=9) at sea level (344 m) and following 14 to 21 days at high altitude (4300 m), and permanent Andean highlanders with (n=6) and without (n=9) EE at high altitude. Vascular function was assessed using intraarterial infusions (3 progressive doses) of acetylcholine (ACh; EDD) and sodium nitroprusside (endothelial-independent dilation) before and after local α+β adrenergic receptor blockade (phentolamine and propranolol). Intraarterial blood pressure, heart rate, and simultaneous brachial artery diameter and blood velocity were recorded at rest and during drug infusion. Changes in forearm vascular conductance were calculated. The main findings were (1) chronic hypoxia reduced EDD in lowlanders (changes in forearm vascular conductance from sea level: ACh1: −52.7±19.6%, ACh2: −25.4±38.7%, ACh3: −35.1±34.7%, all P ≤0.02); and in Andeans with EE compared with non-EE (changes in forearm vascular conductance at ACh3: −36.4%, P =0.007). Adrenergic blockade fully restored EDD in lowlanders at high altitude, and normalized EDD between EE and non-EE Andeans. (2) Chronic hypoxia had no effect on endothelial-independent dilation in lowlanders, and no differences were detected between EE and non-EE Andeans; however, EID was increased in the non-EE Andeans after adrenergic blockade ( P =0.012), but this effect was not observed in the EE Andeans. Conclusions: These data indicate that chronic hypoxia reduces EDD via heightened α-adrenergic signaling in lowlanders and in Andeans with EE. These vascular mechanisms have important implications for understanding the physiological consequences of acute and chronic high altitude adaptation.

Global REACH 2018: The carotid artery diameter response to the cold pressor test is governed by arterial blood pressure during normoxic but not hypoxic conditions in healthy lowlanders and Andean highlanders

“…Unexpectedly, the absolute and relative circulatory responses were the same between sea level and high altitude in lowlanders; such findings were, however, consistent with the similar indexes of CCA stiffness that were observed. These data indicate that the CCA diameter response to the CPT might not accurately represent vascular ‘health’ at high altitude, because other established methods of vascular function, such as brachial artery flow‐mediated dilatation (Tremblay et al., 2018) or the forearm vascular response to acetylcholine (Tymko et al., 2020b), have demonstrated that vascular function is reduced at high altitude >4000 m a.s.l. in healthy lowlanders (also reviewed by Tymko et al., 2019).…”

Mitochondria antioxidant protection against cardiovascular dysfunction programmed by early‐onset gestational hypoxia

“…53 Evidence derived from studies of adult men at high altitude has established that exposure to chronic hypoxia induces endothelial dysfunction mediated in part through heightened adrenergic vasoconstrictor signaling. 54 This effect of chronic hypoxia on adrenergic pathways innervating peripheral blood vessel resistance can be triggered early in life, leading to heightened adrenergic vasoconstrictor signaling in the embryonic or fetal periods, [55][56][57][58] as well as permanently in adult offspring. 13,59,60 For instance, chronically hypoxic fetal sheep have enhanced plasma catecholamine and α 1adrenergic peripheral vasoconstrictor responses to acute stress.…”

Global REACH 2018: the adaptive phenotype to life with chronic mountain sickness and polycythaemia

“…Hypoxaemia and polycythaemia may affect arterial blood pressure through sympathetic hyperactivity (Tymko et al, 2020b), increased peripheral vascular resistance, decreased endothelial function via altered vascular shear stress (de Simone et al, 1990) or increased adrenergic signalling, all of which increase the risk of hypertensive disease (Corante et al, 2018). As reported previously by our group using the microneurographic technique (Tymko et al, 2020b), MSNA burst frequency (P = 0.035) and burst incidence (P = 0.013) were higher in the semi-recumbent position in CMS+ compared with healthy Andeans (Fig. 3A-C).…”