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

Abstract

E rectile dysfunction (ED) is characterized by the inability to develop or maintain penile erection during sexual activity.1 In healthy subjects, penile erection depends on highly coordinated responses, involving relaxation of the pre-and intrapenile vasculature, leading to increased penile blood flow, increased intracavernosal pressure, and penile tumescence. 2,3 Arterial blood flow to the corpus cavernosum originates from the internal iliac arteries, courses to the internal pudendal arteries (IPA), and terminates in the bilateral cavernous arteries. Functional and structural changes in the IPA lead to ED. 4 Diabetes mellitus (DM) is an important risk factor for ED. Over 50% of men with DM develop ED. [5][6][7] In humans, DM is associated with stenosis and occlusion of IPA, which can compromise blood inflow to the corpora cavernosa and, consequently, impair erectile function. 8,9 Abnormalities in IPA are found in 36.7% of diabetic patients. 10 Although it may be expected that IPA display DM-associated dysfunction, 11 almost no studies have addressed the function of IPA in DM. 12 Hyperglycemia, hyperlipidemia, and inflammation, 3 main metabolic abnormalities in DM, induce reactive oxygen species (ROS) generation and oxidative stress. 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.17 IncreasedAbstract-Oxidative stress plays an important role in diabetes mellitus (DM)-associated vascular injury. DM is an important risk factor for erectile dysfunction. Functional and structural changes in internal pudendal arteries (IPA) can lead to erectile dysfunction. We hypothesized that downregulation of nuclear factor E2-related factor 2 (Nrf2), consequent to increased nicotinamide adenine dinucleotide phosphate oxidase 1 (NOX1)-derived reactive oxygen species (ROS), impairs IPA function in DM. IPA and vascular smooth muscle cells from C57BL/6 (control) and NOX1 knockout mice were used. DM was induced by streptozotocin in C57BL/6 mice. Functional properties of IPA were assessed using a myograph, protein expression and peroxiredoxin oxidation by Western blot, RNA expression by polymerase chain reaction, carbonylation by oxyblot assay, ROS generation by lucigenin, nitrotyrosine, and amplex red, and Rho kinase activity and nuclear accumulation of Nrf2 by ELISA. IPA from diabetic mice displayed increased contractions to phenylephrine (control 138.5±9.5 versus DM 191.8±15.5 Nuclear factor E2-related factor 2 (Nrf2) is the mai...

The Sulforaphane and pyridoxamine supplementation normalize endothelial dysfunction associated with type 2 diabetes

“…Importantly, GK rats show a depletion of Nrf2 at the vascular level. In accordance, reduced levels of Nrf2 have been observed in mice diabetic arteries and human cardiac tissues 38 , 46 – 48 . Additionally, previous studies have suggested that aging is associated with Nrf2 dysfunction in the vasculature, which likely exacerbates age-related cellular oxidative stress and increases sensitivity of aged vessels to oxidative stress-induced cellular damage 49 .…”

ER stress and Rho kinase activation underlie the vasculopathy of CADASIL

“…RhoA/Rho kinase signaling influences VSMC contraction, growth, and cytoskeletal organization and is an important regulator of Ca 2+ -independent vasocontraction and endothelium-independent vasorelaxation, processes that were impaired in CADASIL VSMCs. Increased Rho kinase activity has been demonstrated in models of vascular dysfunction (47,48) and has been suggested as a therapeutic target in cerebral vascular disorders in patients with ischemic stroke and cerebrovascular disorders (49,50). We advance this notion and suggest that Rho kinase plays a role in VSMC dysfunction in CADA-SIL.…”

Oxidative Stress, Inflammation, and Vascular Aging in Hypertension

“…In models of diabetes mellitus-induced accelerated vascular aging and erectile dysfunction, Nrf2-Nox interaction, is key, as Nrf2 downregulation increases Nox1 (NADPH oxidase 1)-derived ROS and consequently impairs vascular function. 38 In this setting, Nrf2 activator, Nox1, and Rho kinase inhibitors normalized vascular function, 38 indicating that Nrf2 is clearly vasoprotective. Similarly, Nrf2 downregulation has been observed in arteries from stroke-prone spontaneously hypertensive rats, 39 which contributes to redoxsensitive vascular dysfunction in hypertension.…”