A pictographic essay on blood and tissue oxygen transport

Butcher

American Journal of Physiology-Heart and Circulatory Physiology

et al. 2016

-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...

Section: H496mentioning

confidence: 99%

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

Butcher

American Journal of Physiology-Heart and Circulatory Physiology

et al. 2016

“…Although this syndrome presently afflicts more than 47 million people in the United States (1, 48), defining specific causes underlying this perfusion/demand mismatch has been challenging, as previous studies in human subjects have determined that alterations to vascular reactivity (12, 13, 15, 31), a progressive structural narrowing of individual vessels (46, 47, 51), and a developing reduction in the density of microvessels within skeletal muscle (38, 58) can all occur during the metabolic syndrome in afflicted individuals. Each of these conditions has the potential to elevate vascular resistance (27, 45) and compromise the ability of skeletal muscle to resist fatigue through impairments in the processes of mass transport and exchange (42,43,49,52).We have recently investigated skeletal muscle vascular and microvascular consequences of evolution of the metabolic syndrome in the obese Zucker rat (OZR), a model of this condition that results from chronic hyperphagia experienced by the animal as a result of a deficient leptin receptor gene (7,8).In adult OZR, we have determined that microvessel density within gastrocnemius muscle is markedly reduced and that this reduction contributes, with a structural narrowing of individual skeletal muscle microvessels (18, 54) and an augmentation in vascular ␣-adrenergic reactivity (17, 55), to elevate the vascular resistance to perfusion and the rate at which skeletal muscle fatigues with elevated metabolic demand (19).Our previous study examining impairments in skeletal muscle perfusion in OZR has suggested that although an enhanced vascular ␣-adrenergic reactivity contributes significantly to reduced blood flow under resting conditions, this process does not play a role in blunting muscle perfusion with more substantial increases in metabolic demand (17). We have also previously determined that an acute amelioration of vascular oxidant stress, substantially elevated in OZR, does not improve functional hyperemia in skeletal muscle, despite considerable improvements in the agonist-induced dilator reactivity of arterioles (19,21,22).…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome

American Journal of Physiology-Regulatory, Integrative and Comp

2005

104

105

This study tested the hypothesis that chronically elevated oxidant stress contributes to impaired active hyperemia in skeletal muscle of obese Zucker rats (OZR) vs. lean Zucker rats (LZR) through progressive deteriorations in microvascular structure. Twelve-week-old LZR and OZR were given 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (tempol) in the drinking water for approximately 4 wk. Subsequently, perfusion of in situ gastrocnemius muscle was determined during incremental elevations in metabolic demand, while a contralateral skeletal muscle arteriole and the gastrocnemius muscle was removed to determine dilator reactivity, vessel wall mechanics, and microvessel density. Under control conditions, active hyperemia was impaired at all levels of metabolic demand in OZR, and this was correlated with a reduced microvessel density, increased arteriolar stiffness, and impaired dilator reactivity. Chronic tempol ingestion improved perfusion during moderate to high metabolic demand only and was associated with improved arteriolar reactivity and microvessel density; passive vessel mechanics were unaltered. Combined antioxidant therapy and nitric oxide synthase inhibition in OZR prevented much of the restored perfusion and microvessel density. In LZR, treatment with N(omega)-nitro-L-arginine methyl ester (L-NAME) hydrochloride and hydralazine (to prevent hypertension) impaired active hyperemia, dilator reactivity, and microvessel density, although arteriolar distensibility was not altered. These results suggest that with the development of the metabolic syndrome, chronic reductions in nitric oxide bioavailability, in part via the scavenging actions of oxidative free radicals, contribute to a loss of skeletal muscle microvessels, leading to impaired muscle perfusion with elevated metabolic demand.

American Journal of Physiology-Heart and Circulatory Physiology

“…In particular, the work of Pries et al (42,43) has identified a network Fahraeus effect that can represent a significant contributor to the ultimate reduction in microvascular hematocrit at successive bifurcations owing to a disproportionate distribution of flow (and therefore, erythrocytes) at arteriolar bifurcations. Under control conditions, those authors suggested that this alone could cause a reduction in microvascular hematocrit approaching 20%, with direct implications for tissue oxygenation (8,52). As the results from the present study clearly indicate that ␥ is increased in the arteriolar networks of OZR (vs. control), it would be logical to speculate that this would result in an exacerbation of the network Fahraeus effect, which, when taken in combination with other contributors to hematocrit reduction [e.g., the vessel Fahraeus effect (15,43) and other hemorheological parameters (5,23,34)], would result in a further reduction of microvascular hematocrit within the networks.…”

Section: H556mentioning

confidence: 99%

Blunted temporal activity of microvascular perfusion heterogeneity in metabolic syndrome: a new attractor for peripheral vascular disease?

Butcher

Goodwill

Stanley

et al. 2013

Butcher JT, Goodwill AG, Stanley SC, Frisbee JC. Blunted temporal activity of microvascular perfusion heterogeneity in metabolic syndrome: a new attractor for peripheral vascular disease? Am J Physiol Heart Circ Physiol 304: H547-H558, 2013. First published December 21, 2012 doi:10.1152/ajpheart.00805.2012.-A key clinical outcome for peripheral vascular disease (PVD) in patients is a progressive decay in skeletal muscle performance and its ability to resist fatigue with elevated metabolic demand. We have demonstrated that PVD in obese Zucker rats (OZR) is partially due to increased perfusion distribution heterogeneity at successive microvascular bifurcations within skeletal muscle. As this increased heterogeneity (␥) is longitudinally present in the network, its cumulative impact is a more heterogeneous distribution of perfusion between terminal arterioles than normal, causing greater regional tissue ischemia. To minimize this negative outcome, a likely compensatory mechanism against an increased ␥ should be an increased temporal switching at arteriolar bifurcations to minimize downstream perfusion deficits. Using in situ cremaster muscle, we determined that temporal activity (the cumulative sum of absolute differences between successive values of ␥, taken every 20 s) was lower in OZR than in control animals, and this difference was present in both proximal (1A-2A) and distal (3A-4A) arteriolar bifurcations. Although adrenoreceptor blockade (phentolamine) improved temporal activity in 1A-2A arteriolar bifurcations in OZR, this was without impact in the distal microcirculation, where only interventions against oxidant stress (Tempol) and thromboxane A2 activity (SQ-29548) were effective. Analysis of the attractor for ␥ indicated that it was not only elevated in OZR but also exhibited severe reductions in range, suggesting that the ability of the microcirculation to respond to any challenge is highly restricted and may represent the major contributor to the manifestation of poor muscle performance at this age in OZR. rodent models of obesity; microcirculation; skeletal muscle blood flow regulation; models of peripheral vascular disease; blood flow heterogeneity; vascular dysfunction WITH ONGOING STUDY, THERE is increasing appreciation that the transition from healthy physiology to disease states represents a change in the overall system of control from an existing normal structure (46). It is also generally unclear whether this transition represents a failure of the healthy system or evolving compensations to attempt to optimize the most critical biological outcomes despite progression of a challenged environment (38, 57). For this reason, a detailed understanding of which major contributing processes to an outcome are altered with pathology and the extent for which these are compensated is critical for developing appropriate therapeutic interventions. Failure to elucidate both the key sites of impairment and the compensatory mechanisms, as well as how these impact functional outcomes, has resulted in poorly targ...