Obesity induced-insulin resistance causes endothelial dysfunction without reducing the vascular response to hindlimb ischemia

Abstract

Impairment of vascular growth is a hallmark of diabetic complications, but the progression and mechanisms are poorly understood. To determine whether obesity and early diabetes impair endothelium-dependent vasodilatation and vascular response to ischemia, microvascular function as well as angiogenic responses to ischemia were assessed in young (C57) and 6-month-old lean mice (old C57), in obese (db-C57) mice, and in mice suffering an early (db-KsJ) and sustained type 2 diabetes (old db-KsJ). Glycemia gradually increased from the db-C57 to the old db-KsJ. Early and established type II diabetes significantly reduced the level of insulin that was significantly increased in obese mice. Endothelial function was assessed in isolated resistance arteries while the angiogenic response induced by unilateral hindlimb ischemia was analyzed, after 28 days, with a laser Doppler flowmeter and angiography. Aging (−21%), obesity (−45%), as well as early (−58%) and sustained type II diabetes (−69%) induced a progressive impairment of the endothelium-dependent relaxation of the gracilis artery. Laser Doppler measurements demonstrated that only early and sustained type II diabetes impaired skin blood flow recovery. Vascular collateralization was reduced with aging and severely impaired in older db-KsJ mice, the two strains of mice in which ischemia reduced eNOS expression. These results demonstrate that endothelial dysfunction induced by obesity is insufficient to alter the angiogenic response to ischemia. Furthermore, the development of frank type II diabetes or increasing age is required to impair the vascular response to hindlimb ischemia. We conclude that additional risk factors or severe endothelial dysfunction may be requisite to impede the angiogenic response to ischemia.

Internal Pudental Artery Dysfunction in Diabetes Mellitus Is Mediated by NOX1-Derived ROS-, Nrf2-, and Rho Kinase–Dependent Mechanisms

“…Oxidative stress, defined as a disturbance in the production of ROS or in the ability of the antioxidant defenses to neutralize ROS, is critically involved in DM-associated complications, including nephropathy, cardiomyopathy, endothelial dysfunction, and ED. 6,[13][14][15] Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) is the main source of ROS in the vasculature. Seven NADPH oxidase isoforms have been identified (NOX1-5, Duox1, Duox2), 16 with nicotinamide adenine dinucleoride phosphate oxidase 1 (NOX1) playing an important role in vascular smooth muscle cell (VSMC) proliferation, migration, and extracellular matrix production.…”

Obesity and Inflammatory Vasculopathy

“…Obesity-induced endothelial dysfunction 14 and a causal involvement of TNF-␣ in endothelial dysfunction are well established, notably also in the coronary circulation. [15][16][17][18] Also, TNF-␣-induced increased formation of reactive oxygen species with subsequent oxidative protein modification is established in cardiomyocytes.…”

Ischemia Impairs Vasodilation in Skeletal Muscle Resistance Artery

“…It is also thought that the injury associated with intermittent claudication could be among the causes for increased inflammatory activity and endothelial dysfunction in PAD patients [16]. One of the most common causes of endothelial dysfunction and inflammation is diabetes mellitus [37,49,50].…”

“…Endothelial dysfunctional could represent a putative basis for agedependent impairments in angiogenesis [55]. Further, collateral numbers and endothelialdependent vasodilation were reduced in adult mice (6mo of age) [37]. Senescent mice, aged 20 months exhibited reduced functional vasodilation, likely due to an increase in concentration of α-adenoreceptors in the microvasculature of an aged mouse [54].…”

“…Through genetic manipulation, different co-morbidities can be induced, such as hypercholesterolemia following the disruption of the genes involved in cholesterol trafficking [37].…”