Non-pharmacological interventions for vascular health and the role of the endothelium

Abstract

The most common non-pharmacological intervention for both peripheral and cerebral vascular health is regular physical activity (e.g., exercise training), which improves function across a range of exercise intensities and modalities. Numerous non-exercising approaches have also been suggested to improved vascular function, including repeated ischemic preconditioning (IPC); heat therapy such as hot water bathing and sauna; and pneumatic compression. Chronic adaptive responses have been observed across a number of these approaches, yet the precise mechanisms that underlie these effects in humans are not fully understood. Acute increases in blood flow and circulating signalling factors that induce responses in endothelial function are likely to be key moderators driving these adaptations. While the impact on circulating factors and environmental mechanisms for adaptation may vary between approaches, in essence, they all centre around acutely elevating blood flow throughout the circulation and stimulating improved endothelium-dependent vascular function and ultimately vascular health. Here, we review our current understanding of the mechanisms driving endothelial adaptation to repeated exposure to elevated blood flow, and the interplay between this response and changes in circulating factors. In addition, we will consider the limitations in our current knowledge base and how these may be best addressed through the selection of more physiologically relevant experimental models and research. Ultimately, improving our understanding of the unique impact that non-pharmacological interventions have on the vasculature will allow us to develop superior strategies to tackle declining vascular function across the lifespan, prevent avoidable vascular-related disease, and alleviate dependency on drug-based interventions.

Keywords: Endothelial; Exercise; Heat; Hypoxia; Ischemic preconditioning; Non-pharmacological intervention; Vascular function.

Fig. 1

Representative flow patterns. Illustration of typical flow patterns seen across different intervention strategies, resting baseline is shown as a dashed line in all plots. a Prolonged elevated flow patterns as are commonly seen during interventions such as steady-state exercise or continuous exposure to heat stimuli (e.g., hot water bathing). b Interval or intermittent increases in flow, separated by a return to baseline, as is typical in interval-based exercise responses or in intermittent exposure to environmental stimuli. c Flow response seen during ischemic preconditioning, typified by a prolonged period of very low flow during the ischemic period, followed by a rapid elevation and steady return towards baseline during the cuff-release period. d Pneumatic compression induced flow patterns modelled on a low-frequency treatment pattern of repeated 4-s inflations and 16-s deflations

Fig. 2

Flow-responsive mechanosensory pathways. Changes in flow are detected within the endothelial cell through several mechanosensory pathways. There are broadly four key signalling cascades regulating gene expression. Membrane bound mechanosensory receptors, including G-protein coupled receptors (GPCR), Piezo1 and transient receptor potential vanilloid-type 4 (TRPV4) ion channels and glycocalyx members (including syndecan and glypican), induce changes in gene expression via the mitogen-activated protein kinase pathway (MEK5/ERK5). In addition, the VE-cadherin–PECAM-1–VEGFR2/3 mechanosensory complex [comprising of VE-cadherin, platelet endothelial cell adhesion molecule 1 (PECAM-1), and vascular endothelial growth factor receptor 2 and 3 (VEGFR2/3)] can induce a cascade of responses, through the activation of Src-dependent phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and subsequent activation of the protein kinase Akt. Integrin-associated pathways can also induce signalling cascade responses via the p130Cas Scaffold and ERK5, either in response to activation via Akt signalling or through detection in changes in extracellular matrix structures in response to flow. Finally, activation of calveolins within membrane calveolae is also capable of inducing vasodilatory responses, via the activation of membrane-bound calcium (Ca²⁺) channels. Cumulatively, these signalling cascades induce changes in gene expression and acute vasodilatory responses via elevation in nitric oxide (NO) and prostacyclin (PGI₂) production. Created with BioRender.com

Fig. 3

Differences in typical response between continuous and disturbed flow models. a Prolonged continuous and elevated flow results in the promotion of a quiescent endothelial cell phenotype through the upregulation of Krüppel-like factor 2 and 4 (KLF2/4) and Nuclear-factor-E2-related factor 2 (Nrf2), while suppressing the activity of Nuclear-factor kappa-B (NF-κB) and Yes-associated protein 1 (YAP), via the array of mechanosensory pathways detailed in Fig. 2. b Disturbed flow, characterised by oscillatory patterns of low or reversing shear stress, activates mechanosensory pathways through many of the same receptors as seen in continuous flow; however, these patterns drive opposing responses to those seen in continuous flow leading to the promotion of a dysfunctional endothelial phenotype. Created in BioRender.com

Fig. 4

Flow patterns within continuous and disturbed cell culture conditions. Illustration of simple flow patterns utilised to induce continuous and disturbed responses within endothelial cells. Mean flow rate induced by each pattern is shown as a dashed line in all plots. Continuous, elevated flow responses can be induced by the application of laminar (a) or pulsatile (b) flow patterns in cell culture. Pulsatile flow can also be utilised to simulate disturbed conditions, by the application of pulsatile profiles at low average flow rate (c), resulting in anterograde and retrograde flow components

Fig. 5

Shared signalling pathways between circulating factors and the proteins they upregulate. Vascular endothelial growth factor (VEGF) and insulin-growth factor (IGF-1) both bind to unique membrane receptors (VEGFR1, VGEFR2/3, and IGF-1R) while sharing common signalling pathways within the endothelium, via the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) and activation of Akt, as well as through the mitogen-activated protein kinase pathway MEK1/2–ERK1/2. These signalling pathways can induce significant upregulation of key proteins including VEGF, heat shock proteins (HSP’s), interleukins, and hypoxia-inducible factor 1 alpha. HSP’s and HIF-1α are also seen to be elevated in response to environmental changes such hypoxia and hyperthermia, and both proteins have to capacity to increase responses to circulating factors via interaction with receptor presentation, signal pathways, or both. Created in BioRender