Bang‐Bang Model for Regulation of Local Blood Flow

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: H497 Peripheral Vascular Disease Risk and Microvascular Dysfmentioning

confidence: 56%

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

The International Journal of Biochemistry & Cell Biology

“…Furthermore, since H 2 O 2 is involved in the regulation of vascular tone and muscle perfusion (Suvorava et al 2005; Saitoh et al 2007; Sindler et al 2009), it is plausible that this oxidant may act as a paracrine signal regulating the local matching between O 2 delivery and demand (Marvar et al 2007; Golub and Pittman 2013). Hence, alterations in mitochondrial redox homeostasis may impair the local regulation of O 2 delivery and exacerbate mitochondrial dysfunction with age.…”

Section: Impact Of Age-related Conditions On Muscle Mitochondrial mentioning

confidence: 99%

Mitochondrial dysfunction and sarcopenia of aging: From signaling pathways to clinical trials

Marzetti

Calvani

Cesari

et al. 2013

484

336

Sarcopenia, the age-related loss of muscle mass and function, imposes a dramatic burden on individuals and society. The development of preventive and therapeutic strategies against sarcopenia is therefore perceived as an urgent need by health professionals and has instigated intensive research on the pathophysiology of this syndrome. The pathogenesis of sarcopenia is multifaceted and encompasses lifestyle habits, systemic factors (e.g., chronic inflammation and hormonal alterations), local environment perturbations (e.g., vascular dysfunction), and intramuscular specific processes. In this scenario, derangements in skeletal myocyte mitochondrial function are recognized as major factors contributing to the age-dependent muscle degeneration. In this review, we summarize prominent findings and controversial issues on the contribution of specific mitochondrial processes – including oxidative stress, quality control mechanisms and apoptotic signaling – on the development of sarcopenia. Extramuscular alterations accompanying the aging process with a potential impact on myocyte mitochondrial function are also discussed. We conclude with presenting methodological and safety considerations for the design of clinical trials targeting mitochondrial dysfunction to treat sarcopenia. Special emphasis is placed on the importance of monitoring the effects of an intervention on muscle mitochondrial function and identifying the optimal target population for the trial.

Experimental Physiology

“…However, certain established and recently developed methods are predicated on the presumption that an individual capillary represents a singular unit of surface area, RBC flux and blood–myocyte exchange. Moreover, depending on the contractile activity of the muscle, the small arterioles may assume a greater (rest) or lesser role (exercise) in blood–tissue O 2 flux (Carvalho & Pittman, 2008; Poole et al 2011; reviewed by Golub & Pittman, 2013). Crucially, none of these complexities is readily apparent from bulk blood flow measurements across the body, limbs or discrete muscles, and yet they must play a commanding role in the efficacy by which the capillary bed subserves its major function(s).…”

Section: Introductionmentioning

confidence: 99%

Skeletal muscle capillary function: contemporary observations and novel hypotheses

Poole

Copp

Ferguson

et al. 2013

120

141

The capillary bed constitutes a vast surface facilitating exchange of O2, substrates and metabolites between blood and organs. In contracting skeletal muscle capillary blood flow and O2 diffusing capacity as well as O2 flux may increase two orders of magnitude above resting. Chronic diseases such as heart failure, diabetes and also sepsis impair these processes leading to compromised energetic, metabolic and ultimately contractile function. Among researchers seeking to understand blood-myocyte exchange in health and the bases for dysfunction in disease there is a fundamental disconnect between microcirculation specialists and many physiologists and physiologist clinicians. Whereas the former observe capillaries and capillary function directly (muscle intravital microscopy) the latter generally use indirect methodologies (e.g., post-mortem tissue analysis, 1-methyl xanthine, contrast enhanced ultrasound, permeability surface area product) and interpret their findings based upon August Krogh’s observations made nearly a century ago. “Kroghian” theory holds that only a small fraction of capillaries support red blood cell (RBC) flux in resting muscle leaving the vast majority to be “recruited” (i.e., initiate RBC flux) during contractions which would constitute the basis for increasing capillary exchange surface area and reducing capillary-mitochondrial diffusion distances. Experimental techniques each have their strengths and weaknesses and often the correct or complete answer to a problem emerges from integration across multiple technologies. Today Krogh’s entrenched “capillary recruitment” hypothesis is challenged by direct observations of capillaries in contracting muscle; something that he and his colleagues could not do. Moreover, in the peer-reviewed scientific literature, application of a range of contemporary physiological technologies including intravital microscopy of contracting muscle, magnetic resonance and near infrared spectroscopy and phosphorescence quenching combined with elegant in situ and in vivo models suggest that the role of the capillary bed, at least in contracting muscle, is subserved without the necessity for de novo capillary recruitment of previously non-flowing capillaries. When viewed within the context of the capillary recruitment hypothesis, this evidence casts serious doubt on the interpretation of those data that are based upon Kroghian theory and indirect methodologies. Thus today a wealth of evidence calls for a radical revision of blood-muscle exchange theory to one in which most capillaries support RBC flux at rest and, during contractions, capillary surface area is “recruited” along the length of previously flowing capillaries. This occurs, in part, by elevating capillary hematocrit and extending the length of the capillary available for blood-myocyte exchange (i.e., longitudinal recruitment). Our understanding of blood-myocyte O2 and substrate/metabolite exchange in health and the mechanistic bases for dysfunction in disease demands no less.