Serum from young, sedentary adults who underwent passive heat therapy improves endothelial cell angiogenesis via improved nitric oxide bioavailability

Abstract

Rationale: Passive heat therapy improves vascular endothelial function, likely via enhanced nitric oxide (NO) bioavailability, although the mechanistic stimuli driving these changes are unknown. Objective: To determine the isolated effects of circulating (serum) factors on endothelial cell function, particularly angiogenesis, and NO bioavailability. Methods and Results: Cultured human umbilical vein endothelial cells (HUVECs) were exposed to serum collected from 20 healthy young (22 ± 1 years) adults before (0 wk), after one session of water immersion (Acute HT), and after 8 wk of either heat therapy (N = 10; 36 sessions of hot water immersion; session 1 peak rectal temperature: 39.0 ± 0.03°C) or sham (N = 10; 36 sessions of thermoneutral water immersion). Serum collected following acute heat exposure and heat therapy improved endothelial cell angiogenesis (Matrigel bioassay total tubule length per frame, 0 wk: 69.3 ± 1.9 mm vs. Acute HT: 72.8 ± 1.4 mm, p = 0.04; vs. 8 wk: 73.0 ± 1.4 mm, p = 0.03), with no effects of sham serum. Enhanced angiogenesis was NO-mediated, as addition of the NO synthase (NOS) inhibitor L-NNA to the culture media abolished differences in tubule formation across conditions (0 wk: 71.3 ± 1.8 mm, Acute HT: 71.6 ± 1.9 mm, 8 wk: 70.5 ± 1.6 mm, p = 0.69). In separate experiments, we found that abundance of endothelial NOS (eNOS) was unaffected by Acute HT serum (p = 0.71), but increased by 8 wk heat therapy serum (1.4 ± 0.1-fold from 0 wk, p < 0.01). Furthermore, increases in eNOS were related to improvements in endothelial tubule formation (r 2 = 0.61, p < 0.01). Conclusions: Passive heat therapy beneficially alters circulating factors that promote NOmediated angiogenesis in endothelial cells and increase eNOS abundance. These changes may contribute to improvements in vascular function with heat therapy observed in vivo.

Cold-Inducible RNA-Binding Protein but Not Its Antisense lncRNA Is a Direct Negative Regulator of Angiogenesis In Vitro and In Vivo via Regulation of the 14q32 angiomiRs—microRNA-329-3p and microRNA-495-3p

“…Therefore, one could imagine that hyperthermia leads to decreased CIRBP expression in the leg, followed by subsequent increases in angiogenesis. Thus far, heat therapy was shown to be of potential benefit to PAD patients by enhancing leg blood flow and improving muscle function [ 33 , 34 ].…”

Effects of repeated local heat therapy on skeletal muscle structure and function in humans

“…The increase in eNOS content and the consequent angiogenic response to whole-body HT appears to be mediated in part by circulating factors. Brunt and coworkers showed that exposing cultured endothelial cells to serum collected from participants who had undergone whole-body HT for 8 weeks increased the abundance of eNOS and endothelial tubule formation (6). Combined, these studies provide compelling evidence implicating nitric oxide (NO) as a critical mediator of heat-induced skeletal muscle angiogenesis.…”

Concurrent adaptations in maximal aerobic capacity, heat tolerance, microvascular blood flow and oxygen extraction following heat acclimation and ischemic preconditioning

“…following HA in both experimental groups, which can be caused by increased capillary growth (Hesketh et al, 2019) or nitric oxide availability (Brunt et al, 2019) following heat therapy. These changes are consistent with the suggestion that heat therapies elicit changes in skeletal muscle metabolism, the peripheral vasculature or a combination of associated factors (Kim et al, 2020).…”