Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation

Abstract

-To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: SpragueDawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A 2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk. rodent models of cardiovascular disease risk; peripheral vascular disease; blood flow regulation; microvascular dysfunction; system biology of microcirculation NEW & NOTEWORTHY Linking peripheral vascular disease (PVD) risk to integrated microvascular dysfunction and health outcomes has been elusive. We used eight models of increasing risk and a multiscale approach to interrogate novel indexes of microvascular function, perfusion/oxygen handling, and outcomes. We demonstrate how elevated PVD risk leads to progressive microvascular "dampening," with clear implications for outcomes.THE PREDOMINANT CONCERN regarding the presence of peripheral vascular disease (PVD) risk factors of increasing severity is that these can lead to the development of pathological characteristics of PVD including myocardial infarction, heart failure, stoke, and/or limb ischemia. These potential outcomes of PVD result in elevations in mortality risk as well as significant reductions in quality of life through a variety of direct and indirect causes (3,45,50) that are predominantly perceived as macrovascular events. These global processes can develop across tissues and organs, leading to the clinica...

Impaired Muscle Oxygenation and Elevated Exercise Blood Pressure in Hypertensive Patients

“…The significant inverse correlation observed between muscle oxygenation and microvascular reactivity indices during arterial occlusion, with the force maintained during the handgrip task, agrees with results in hypertensive rodents, showing a link between skeletal muscle microvascular dysfunction and alterations in performance outcomes. 12 Whether patients with more severe hypertension would be unable to achieve perfusion and exhibit faster signs of exercise intolerance requires further investigation.…”

“…50 Postulated mechanisms for these dysfunctions include: (1) the capillary rarefaction and increased perfusion heterogeneity in hypertensives impair flow and oxygen delivery to the working muscles; thus, a greater increase in BP is required to achieve perfusion, and (2) the structural alterations in the resistance vasculature may act as a vascular amplifier that further enhances the effects of a hypertensive stimulus, such as exercise. 12,50 In addition, the impaired oxidative capacity suggestive of mitochondrial dysfunction/uncoupling in the skeletal muscle of hypertensive patients could lead to an increase in reactive oxygen species, reducing endothelial NO synthase, and resulting in a decrease NO bioavailability. 46 The increased oxidative stress and inflammation further reduces NO, promoting endothelial dysfunction within the small vessels' wall and impairing vasodilation in exercising muscles.…”

“…11 However, information on skeletal muscle microvascular alterations and oxidative capacity in hypertension has been obtained mainly from animal models or ex vivo from human biopsies. 8,[12][13][14] Although the above results imply that oxygen delivery, exchange, and utilization within the skeletal muscles may be impaired in hypertensive individuals versus normotensives, information under in vivo conditions is lacking. In addition, in vivo studies reporting reduced vascular reactivity in hypertensive patients examined mainly whole limbs (eg, forearm plethysmography), conduit arteries (by flow-mediated dilation), and cutaneous microvessels.…”

Time-dependent Behavior of Microvascular Blood Flow and Oxygenation: a Predictor of Functional Outcomes

“…Recently, Frisbee and others [2] have shown that attenuation of these flow patterns may be a major contributor to disease risk. They argue that if we are to understand network functionality and flexibility in cardiovascular (CV) and metabolic (Met) disease it is important to obtain quantitative in vivo information on the temporal behaviour and spatial distribution of microvascular perfusion.…”

“…More recently, chaotic network attractor analysis [17,18] has revealed a declining adaptability of microvascular flow patterns in rodent models of CV and Met disease [2]. However, the relationship between the non-linear oscillatory dynamics of the BF signal, microvascular network perfusion heterogeneity and adaptability (and their impact on microvascular pathology) has yet to be fully elucidated.…”