Distinct temporal phases of microvascular rarefaction in skeletal muscle of obese Zucker rats

Abstract

lution of metabolic syndrome is associated with a progressive reduction in skeletal muscle microvessel density, known as rarefaction. Although contributing to impairments to mass transport and exchange, the temporal development of rarefaction and the contributing mechanisms that lead to microvessel loss are both unclear and critical areas for investigation. Although previous work suggests that rarefaction severity in obese Zucker rats (OZR) is predicted by the chronic loss of vascular nitric oxide (NO) bioavailability, we have determined that this hides a biphasic development of rarefaction, with both early and late components. Although the total extent of rarefaction was well predicted by the loss in NO bioavailability, the early pulse of rarefaction developed before a loss of NO bioavailability and was associated with altered venular function (increased leukocyte adhesion/rolling), and early elevation in oxidant stress, TNF-␣ levels, and the vascular production of thromboxane A2 (TxA2). Chronic inhibition of TNF-␣ blunted the severity of rarefaction and also reduced vascular oxidant stress and TxA 2 production. Chronic blockade of the actions of TxA2 also blunted rarefaction, but did not impact oxidant stress or inflammation, suggesting that TxA 2 is a downstream outcome of elevated reactive oxygen species and inflammation. If chronic blockade of TxA 2 is terminated, microvascular rarefaction in OZR skeletal muscle resumes, but at a reduced rate despite low NO bioavailability. These results suggest that therapeutic interventions against inflammation and TxA 2 under conditions where metabolic syndrome severity is moderate or mild may prevent the development of a condition of accelerated microvessel loss with metabolic syndrome. skeletal muscle perfusion; vascular remodeling; vascular reactivity; rodent models of obesity; nitric oxide bioavailability; chronic inflammation EPIDEMIOLOGICAL STUDIES HAVE clearly and consistently demonstrated that both the incidence and prevalence of the metabolic syndrome is continuing to increase in Western society and in most developed economies worldwide (4, 9, 24). Although each of the constituent systemic pathologies (e.g., impaired glycemic control, atherogenic dyslipidemia, hypertension, obesity) have been well documented to increase the risk for development of impaired vascular structure/function and peripheral vascular disease (PVD) (10,11,13,14,16,25,29,45), the significance of this multi-pathology state is that it increases the risk for individuals to develop PVD well beyond that for any single contributing element. Given the impact of PVD on life expectancy, quality of life, depression, and the direct (health care) and indirect (lost productivity) economic costs to society (3, 41, 44), considerable emphasis has been placed on not only the study of PVD and its contributing elements in human subjects but also for the detailed investigation of appropriate animal models of vasculopathy in the metabolic syndrome (1, 49, 51). However, although the existing literature is replet...

Impaired Tissue Oxygenation in Metabolic Syndrome Requires Increased Microvascular Perfusion Heterogeneity

“…Given the previously demonstrated impairments to vascular/arteriolar function in the skeletal muscle of OZR [16], the progressive rarefaction of the microvascular networks [34] and the reduction to bulk perfusion to the skeletal muscle across metabolic intensities [11], impaired oxygen transport is not particularly surprising. However, combining our present model results with our previous findings of heterogeneous microvascular blood flow distribution using both direct microvascular visualization [16–18] and tracer washout kinetics [19], an alternate interpretation of literature data suggests that increased muscle fatigue in OZR may also reflect an increasingly heterogeneous distribution of perfusion within microvascular networks.…”

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

“…2 0 0 7 ) , thromhospondin-1 (Thbs1) (Lawler 2002), Thbs2 (Volpert et al 1995), the potent anti-angiogenic chemokine platelet factor 4 (Pf4) (Bikfalvi 2004); vasohibin-1 (Vash1), which is a newly recognized (Takano et al 2014), Adamts1 ("a disintegrin and metalloproteinase with thrombospondin motifs 1"), which inhibits angiogenesis (Lee et al 2006) by suppressing endothelial cell proliferation; Col18a1, whose expression level impacts endostatin signaling and endothelial angiogenic capacity (Li and Olsen 2004) (endostatin, a potent inhibitor of angiogenesis, is a 20-kDa C-terminal fragment derived from type XVIII collagen); semaphorin-3F (Sema3f) (Ungvari et al 2011b;Frisbee et al 2007); tenomodulin (Tnmd) (Oshima et al 2003); brainspecific angiogenesis inhibitor 1 (Bai1; also known as adhesion G protein-coupled receptor B1 [ADGRB1]) (Nishimori et al 1997); chromogranin A (Chga), which encodes the precursor to several angiogenesis inhibitor peptides including vasostatin-1 and vasostatin-2 (Helle and Corti 2015) and maspin ("mammary serine protease inhibitor"; encoded by the Serpinb5 gene (Qin and Zhang 2010). Figure 7 shows the expression of Tnfa, whose overproduction has been causally linked to microvascular rarefaction (Frisbee et al 2014); Tgfb1, which regulates multiple aspects of the angiogenic process and contributes to hypertension-induced microvascular rarefaction in the heart (Koitabashi et al 2011); Tgfa; angiogenin (Ang, also known as ribonuclease 5), which is a potent stimulator of angiogenesis and an inhibitor of endothelial apoptosis; Edil3 (EGF-like repeats and discoidin Ilike domains 3), which encodes a glycoprotein secreted by endothelial cells that regulates apoptosis, cell migration (Zhong et al 2003) and induces cerebral angiogenesis in mice (Fan et al 2008); midkine (Mdk, also known as neurite growth-promoting factor 2 or NEGF2), which is a pleiotropic growth factor regulating cell proliferation, cell migration and promoting angiogenesis (Mashour et al 2001 [HB-GAM]), which is a pro-angiogenic growth factor that is structurally related to midkine and whose expression in the adult brain is induced by ischemia; Tymp (thymidine phosphorylase, also known as platelet-derived endothelial cell growth factor [ECGF1], which stimulates endothelial cell proliferation and induces angiogenesis in the brain (Hayashi et al 2007); platelet endothelial cell adhesion molecule (Pecam1; also known as CD31), which confers pro-angiogenic effects (Park et al 2015)<...>…”

Obesity and Critical Illness

“…Thus, it is vital to be aware of the baseline characteristics in an obese animal when choosing a model for a critical illness study, and potential non-specific impacts such as hyperglycemia and hyperleptinemia on innate immune responses from these different baseline parameters, for example, the fasting hyperglycemia in Zucker diabetic fatty rats vs. normal fasting glucose in obese Zucker rats, and the lack of leptin in ob-/ob-mice vs. high leptin in db-/db-mice. Also, investigators should be aware of the impact of aging on cardiovascular and immune systems in the obese animals models (17). Regardless these discrepancies, metabolic disorders such as hyperlipidemia and postprandial hyperglycemia are commonly observed in obese models and appear to play a critical role in the development of chronic metaflammation and cardiovascular dysfunction.…”