Recent experimental evidence suggests that arterial insufficiency precedes the structural and functional changes in corpora cavernosa (CC) leading to organic erectile dysfunction (ED). The present review gives an overview of the physiological factors involved in the regulation of penile vasculature. Sympathetic nerves maintain flaccidity and tonically released noradrenaline induces vasoconstriction of both arteries and veins through a 1 -and a 2 -postsynaptic receptors and downregulates its own release and that of nitric oxide (NO) through a 2 -presynaptic receptors. The sympathetic cotransmitter neuropeptide Y (NPY) modulates noradrenergic vasoconstriction in penile small arteries by both enhancing and depressing noradrenaline contractions through Y 1 -and Y 2 -postsynaptic and a NO-independent atypical endothelial receptor, respectively. Activation of a 1 -adrenoceptors involves both Ca 2 þ influx through L-type and receptor-operated Ca 2 þ channels (ROC) and Ca 2 þ sensitization mechanisms mediated by protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase (RhoK). In addition, RhoK can regulate Ca 2 þ entry in penile arteries upon receptor stimulation. Vasodilatation of penile arteries and large veins during erection is mediated by neurally released NO. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining penile arteries activates endothelial NO production through Akt phosphorylation of endothelial NO synthase (eNOS). NO stimulates guanylate cyclase and increased cyclic guanin 3 0 -monophosphate (cGMP) levels in turn activate protein kinase G (PKG), which enhances K þ efflux through Ca 2 þ -activated (K Ca ) and voltage-dependent Ca 2 þ (K v ) channels in penile arteries and veins, respectively. PKG-mediated decrease in Ca 2 þ sensitivity and its regulation by RhoK remains to be clarified in penile vasculature. Phosphodiesterase type 5 (PDE5) inhibitors are potent vasodilators of penile resistance arteries and increase the content and effects of basally released endothelial NO. Endothelium-dependent relaxations of penile small arteries also include an endothelium-derived hyperpolarizing factor (EDHF)-type response, which is impaired in diabetes and hypertension-associated ED. Locally produced contractile and relaxant prostanoids regulate penile venous and arterial tone, respectively. The latter activates prostaglandin I (IP) and prostaglandin E (EP) receptors coupled to adenylate cyclase and to the increase of cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates K þ efflux through ATPsensitive K þ (K ATP ) channels. There is a crosstalk between the cGMP and cAMP signaling pathways in penile small arteries. Relevant issues such as the mechanisms underlying the excitationsecretion coupling of the endothelial cells, as well as those involved in cell proliferation and vascular remodeling of the penile vasculature remain to be elucidated. In addition, only few studies have investigated the changes in structure and function of penile a...

Obesity is a metabolic disorder of increasing prevalence worldwide and a risk factor for the development of insulin resistance (IR), metabolic syndrome and type 2 diabetes. Obesity is related to endothelial dysfunction through indirect mechanisms such as IR and the associated risk factors, and through direct mechanisms including the production of proinflammatory adipokines and elevated levels of free fatty acids (FFAs) by adipose tissue. Both clinical and experimental studies using genetic and diet-induced animal models of obesity have consistently shown impaired metabolic, agonistor flow-induced vasodilatations correlated with the amount of visceral adipose tissue and improved by dietary interventions and exercise. Compromised bioavailability of NO due to oxidative stress emerges as a main cause of endothelial dysfunction in obesity. Inflamed adipose tissue due to hypoxia, and in particular perivascular adipose tissue (PVAT), secrete larger amounts of reactive oxygen species (ROS) and adipokines that deteriorate NO signaling pathways. Abnormal production and activity of the vasoconstrictor/proatherogenic peptide endothelin-1 (ET-1) is also a hallmark of the obesity- associated endothelial dysfunction. Obesity, and in particular visceral obesity, is one of the main causes of IR, and the pathogenic factors that induce endothelial dysfunction in the earlier stages of obesity will further deteriorate the insulin signaling pathways in endothelial cells thus leading to blunted vasodilatation and abnormal capillary recruitment and substrate delivery by insulin to the target tissues. The present review is an attempt to summarize the current knowledge and the latest novel findings on the pathogenic mechanisms underlying endothelial dysfunction in obesity, in particular the local contribution of oxidative stress and inflammatory response from PVAT, and its role in the obesity-associated cardiovascular and metabolic complications.

Erectile dysfunction frequently coexists with coronary artery disease and has been proposed as a potential marker for silent coronary artery disease in type 2 diabetes. In the present study, we comparatively assessed the structural and functional changes of both penile arteries (PAs) and coronary arteries (CAs) from a prediabetic animal model. PAs and CAs from 17-to 18-wk-old obese Zucker rats (OZRs) and from their control counterparts [lean Zucker rats (LZRs)] were mounted in microvascular myographs to evaluate vascular function, and stained arteries were subjected to morphometric analysis. Endothelial nitric oxide (NO) synthase (eNOS) protein expression was also assessed. The internal diameter was reduced and the wall-to-lumen ratio was increased in PAs from OZRs, but structure was preserved in CAs. ACh-elicited relaxations were severely impaired in PAs but not in CAs from OZRs, although eNOS expression was unaltered. Contractions to norepinephrine and 5-HT were significantly enhanced in both PAs and CAs, respectively, from OZRs. Blockade of NOS abolished endothelium-dependent relaxations in PAs and CAs and potentiated norepinephrine and 5-HT contractions in arteries from LZRs but not from OZRs. The vasodilator response to the phosphodiesterase 5 inhibitor sildenafil was reduced in both PAs and CAs from OZRs. Pretreatment with SOD reduced the enhanced vasoconstriction in both PAs and CAs from OZRs but did not restore ACh-induced relaxations in PAs. In conclusion, the present results demonstrate vascular inward remodeling in PAs and a differential impairment of endothelial relaxant responses in PAs and CAs from insulin-resistant OZRs. Enhanced superoxide production and reduced basal NO activity seem to underlie the augmented vasoconstriction in both PAs and CAs. The severity of the structural and functional abnormalities in PAs might anticipate the vascular dysfunction of the more preserved coronary vascular bed. vascular remodeling; endothelial dysfunction; coronary artery; penile artery; erectile dysfunction ERECTILE DYSFUNCTION (ED) is currently considered an early clinical manifestation of a more generalized vascular disease due to its high prevalence in patients with cardiovascular risk factors including diabetes, hypertension, hyperlipidemia, and tobacco abuse (32,46). ED is a common complication and an important cause of decreased quality of life in men with diabetes, and its prevalence is three times higher in type 1 and type 2 diabetic patients than in the general population (18,48).Growing epidemiological evidence associates the subsequent risk of ED with the presence of risk factors for coronary artery disease (CAD) such as obesity, hypertension, and dyslipidemia (32, 34). On the other hand, the rate of ED in patients with CAD is as high as 42-57%, and the incidence of ED in diabetic patients with silent ischemia is 34.8% versus 4.7% in those without silent ischemia (16,32,34). This has recently led to the suggestion that ED could be a potential marker for silent CAD in type 2 diabetes mellitus patie...

Alterations in the flow of blood to and from the penis are thought to be the most frequent causes of male erectile dysfunction and, therefore, the present review focuses on the penile vasculature. In the flaccid state, tonic noradrenaline release from the sympathetic nerves contracts penile arterial and corporal smooth muscle through activation of postjunctional α₁-adrenoceptors, both by increasing intracellular calcium and by enhancing the sensitivity of the contractile apparatus for calcium. In addition, noradrenaline inhibits vasodilatatory neurotransmitter release by prejunctional α₂-adrenoceptors. The exact role of the sympathetic neurotransmitters, neuropeptide Y and adenosine 5′-triphosphate, in erection is largely unknown. Penile vasodilatation during erection is mediated by nitric oxide (NO) through activation of guanylyl cyclase in the smooth muscle layer, followed by increases in cyclic guanosine monophosphate lowering of intracellular calcium and desensitisation of the contractile apparatus for calcium. Acetylcholine, vasoactive intestinal peptide as well as peptides in sensory nerves probably also play a role in penile vasodilation. Increased flow through the penile arteries stimulates the endothelium leading to release of NO, prostanoids and a non-NO non-prostanoid factor, and as such enhances the vasodilatation, while the role of endothelium-derived contractile factors in penile vasoconstriction is not clear. Erectile dysfunction shares arterial risk factors with ischaemic heart disease, and diabetes, age, and hypercholesterolaemia are associated with impairment of both neurogenic and endothelium-dependent vasodilator mechanisms in corpus cavernosum. Only few studies have investigated the impact of these risk factors on the penile vasculature, although recent evidence suggests that arterial insufficiency precedes changes in corpus cavernosum leading to erectile dysfunction.

Oxidative stress-associated endothelial dysfunction is a key pathogenic factor underlying the microvascular complications of metabolic disease. NADPH oxidase (Nox) is a major source of oxidative stress in diabetic nephropathy and chronic kidney disease, despite Nox4 and Nox2 have been identified as relevant sources of vasodilator endothelial H2O2.The present study was sought to investigate the role of Nox enzymes in renal vascular oxidative stress and endothelial dysfunction in a rat model of genetic obesity. Endothelial function was assessed in intrarenal arteries of obese Zucker rats (OZR) and their counterparts lean Zucker rats (LZR) mounted in microvascular myographs, and superoxide (O2.-) and H2O2 production were measured. Impaired endothelium-dependent relaxations to acetylcholine (ACh) were associated to augmented O2.- generation, but neither ROS scavengers nor the Nox inhibitor apocynin significantly improved these relaxant responses in renal arteries of OZR. Whereas NO contribution to endothelial relaxations was blunted, catalase-sensitive non-NO non-prostanoid relaxations were enhanced in obese rats. Interestingly, NADPH–dependent O2.- production was augmented while NADPH-dependent H2O2 generation was reduced, and cytosolic and mitochondrial SOD were up-regulated in kidney of obese rats. Nox4 was down-regulated in renal arteries and Nox4-dependent H2O2 generation and endothelial relaxation were reduced in OZR. Up-regulation of both Nox2 and Nox1 was associated with augmented O2.- production but reduced H2O2 generation and blunted endothelial Nox2-derived H2O2-mediated in obese rats. Moreover, increased Nox1-derived O2.- contributed to renal endothelial dysfunction in OZR. In summary, the current data support a main role for Nox1-derived O2.- in kidney vascular oxidative stress and renal endothelial dysfunction in obesity, while reduced endothelial Nox4 expression associated to decreased H2O2 generation and H2O2–mediated vasodilatation might hinder Nox4 protective renal effects thus contributing to kidney injury. This suggests that effective therapies to counteract oxidative stress and prevent microvascular complications must identify the specific Nox subunits involved in metabolic disease.