The association between erectile dysfunction and cardiometabolic disease is well characterized; men are often diagnosed with cardiovascular disease 2-5 years following the incidence of erectile ...dysfunction. There is evidence that this relationship may also exist for cardiometabolic diseases and female sexual dysfunction (FSD) - particularly sexual arousal disorders.
To provide a summary of the preclinical literature related to the evidence of FSD in animal models of cardiometabolic diseases and indicate where further research is needed.
A detailed Medline search of peer-reviewed publications was performed on the associations between animal models of cardiometabolic diseases, FSD and underlying mechanisms.
A summary of the preclinical evidence of FSD in animal models of cardiometabolic diseases.
Common methods for assessing female sexual arousal and physiology in animal models include: 1) behavioral assessments (apomorphine-induced genital vasocongestive arousal; hormone-dependent lordosis), 2) nerve-mediated vaginal and clitoral blood flow, 3) pudendal artery, vaginal and clitoral smooth muscle physiology (vasoreactivity and molecular biology), 4) morphology of genital tissues. Twenty-eight studies examined female animal models of atherosclerosis, hypertension, diabetes (type 1 and 2) and obesity. They showed functional alterations, including decreased lordosis, lubrication, or vaginal and clitoral blood flow, and structural impairments, such as increased clitoral and vaginal fibrosis. Several possible mechanisms have been described including increased TGF-β, renin angiotensin system and endothelin/rho-kinase signaling, increased reactive oxygen species, and decreased nitric oxide/cGMP signaling.
In line with existing clinical studies, preclinical evidence supports that cardiometabolic diseases alter female genital tissue's function and structure leading to impaired sexual arousal.
This masterclass paper gives an overview of the preclinical research assessing FSD in cardiometabolic disease. Limitations include the small number of studies that have assessed sexual function and arousal in female cardiometabolic animal models.
Preclinical evidence exists showing cardiometabolic diseases alter the structure and function of female genital tissues. However, similar to clinical studies, there are few studies to draw from, particularly in models of type 2 diabetes, obesity and metabolic syndrome. More studies are required using optimized animal models and methodology to confirm the mechanisms underlying cardiometabolic disease-induced FSD. Angulo J, Hannan JL. Cardiometabolic Diseases and Female Sexual Dysfunction: Animal Studies. J Sex Med 2022;19:408-420.
Pathophysiology of erectile dysfunction Matsui, Hotaka; Sopko, Nikolai A; Hannan, Johanna L ...
Current drug targets,
05/2015, Letnik:
16, Številka:
5
Journal Article
Recenzirano
Erectile dysfunction (ED) is a major health problem as the population ages. Basic science research for the last two decades has expanded the knowledge on ED and identified several key molecular ...changes associated with the pathogenesis of ED, including nitric oxide (NO) / cyclic guanosine monophosphate (cGMP) / protein kinase G (PKG) pathway, RhoA/Rho-associated protein kinase (ROCK) signaling pathway, reactive oxygen species (ROS), renin-angiotensin system (RAS) and tumor necrosis factor-alpha (TNF-α). The causes of ED are classified into aging, vasculogenic, neurogenic, endocrinological, drug-induced and psychogenic. ED is often associated with systemic diseases, such as diabetes and cardiovascular diseases. In this review, we will review the molecular mechanisms of ED and known mechanisms behind ED associated with systemic diseases.
Erectile dysfunction (ED) is a common disorder that affects a quarter of US men, and has many causes, including endothelial impairment, low testosterone levels, prior surgical manipulation, and/or ...psychogenic components. Penile erection is a complex process requiring neurally mediated relaxation of arteriolar smooth muscle and engorgement of cavernosal tissues, mediated by nitric oxide (NO). Current medical therapies for ED largely seek to maximize endogenous NO signalling. Certain aetiologies, including diabetes, are difficult to treat with current modalities, emphasizing the need for new molecular targets. Research has demonstrated the importance of RhoA-Rho-associated protein kinase (ROCK) signalling in maintaining a flaccid penile state, and inhibition of RhoA-ROCK signalling potentiates smooth-muscle relaxation in an NO-independent manner. The mechanisms and effects of RhoA-ROCK signalling and inhibition suggest that the RhoA-ROCK pathway could prove to be a new therapeutic target for the treatment of ED.
Androgen deprivation therapy is a common prostate cancer treatment which causes men to have castrate levels of testosterone. Unfortunately, most testosterone deficient patients will suffer severe ...erectile dysfunction (ED) and have no effective ED treatment options. Testosterone deficiency causes endothelial dysfunction and impairs penile vasodilation necessary to maintain an erection. Recent evidence demonstrates testosterone activates androgen receptors (AR) and generates nitric oxide (NO) through the Akt-endothelial NO synthase (eNOS) pathway; however, it remains unknown how castration impacts this signaling pathway.
In this study, we used a surgically castrated rat model to determine how castration impacts ex vivo internal pudendal artery (IPA) and penile relaxation through the Akt-eNOS pathway.
Unlike systemic vasculature, castration causes significant IPA and penis endothelial dysfunction associated with a 50% AR reduction. Though testosterone and acetylcholine (ACh) both phosphorylate Akt and eNOS, castration did not affect testosterone-mediated IPA and penile Akt or eNOS phosphorylation. Surprisingly, castration increases ACh-mediated Akt and eNOS phosphorylation but reduces the eNOS dimer to monomer ratio. Akt inhibition using 10DEBC preserves IPA eNOS dimers. Functionally, 10DEBC reverses castration induced ex vivo IPA and penile endothelial dysfunction.
These data demonstrate how castration uncouples eNOS and provide a novel strategy for improving endothelial-dependent relaxation necessary for an erection. Further studies are needed to determine if Akt inhibition may treat or even prevent ED in testosterone deficient prostate cancer survivors.
•Castration reduces penile and pre-penile vascular endothelial-dependent relaxation.•Castration decreases the penile eNOS dimer to monomer ratio.•Ex vivo Akt inhibition reverses ex vivo castration induced penile endothelial damage.
Purpose Bilateral cavernous nerve injury results in up-regulation of ROCK signaling in the penis. This is linked to erectile dysfunction in an animal model of post-prostatectomy erectile dysfunction. ...We evaluated whether daily treatment with the ROCK inhibitor Y-27632 (Tocris Bioscience, Ellisville, Missouri) would prevent erectile dysfunction in a rat model of bilateral cavernous nerve injury. Materials and Methods Sprague-Dawley® rats underwent surgery to create sham (14) or bilateral (27) cavernous nerve injury. In the injury group 13 rats received treatment with Y-27632 (5 mg/kg twice daily) and 14 received vehicle. At 14 days after injury, rats underwent cavernous nerve stimulation to determine erectile function. Penes were assessed for neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase. ROCK2 was assessed by Western blot. Cyclic guanosine monophosphate was determined by enzyme-linked immunosorbent assay. Cavernous homogenates were tested for ROCK and protein kinase G enzymatic activity. Penile apoptosis was evaluated using the Apostain technique (Alexis, San Diego, California). Data were analyzed on ROCK using ANOVA and the t test. Results While erectile function was decreased in rats with bilateral cavernous nerve injury, daily administration of Y-27632 improved erectile responses. Injury decreased neuronal and nitric oxide synthase membrane-endothelial nitric oxide synthase but ROCK2 was significantly increased. Y-27632 treatment restored neuronal nitric oxide synthase, nitric oxide synthase membrane-endothelial nitric oxide synthase and cyclic guanosine monophosphate levels, and protein kinase G activity. Treatment significantly decreased ROCK2 protein and ROCK activity. There were significantly fewer apoptotic cells after treatment than in injured controls. Conclusions These results provide evidence for up-regulation of the RhoA/ROCK signaling pathway with detrimental effects on erectile function after bilateral cavernous nerve injury. ROCK inhibition improved erectile dysfunction associated with bilateral cavernous nerve injury by preserving penile nitric oxide bioavailability and decreasing penile apoptosis.
Obesity can lead to cardiovascular disease, diabetes, and erectile dysfunction (ED), which decreases overall quality of life. Mechanisms responsible for obesity-induced ED are unknown. Current mouse ...models of high-fat diet (HFD)-induced obesity yield conflicting results. Genetic variants among common "wild type" strains may explain contradictory data. Adult male C57BL/6N and 6J mice were fed a 45% HFD for 12 weeks. Weekly food intake, weight gain, and body-fat percentage were measured. After 12 weeks, ex vivo vascular reactivity was measured in aortas, internal pudendal arteries, and penises. We assessed smooth muscle contractility, endothelial-dependent and -independent relaxation, and penile neurotransmitter-mediated relaxation. C57BL/6N mice developed greater obesity and glucose sensitivity compared to C57BL/6J mice. Aortas from both strains that fed a HFD had decreased contraction, yet contraction was unchanged in HFD pudendal arteries and penises. Interestingly, endothelial-dependent and -independent relaxation was unchanged in both systemic and penile vasculature. Likewise, HFD did not impair penile neurotransmitter-mediated relaxation. Both strains fed 12 weeks of HFD-developed obese phenotypes. However, HFD did not impair pre-penile or penile smooth muscle vasoreactivity as demonstrated in previous studies, suggesting that this preclinical model does not accurately represent the clinical phenotype of obesity-induced ED.
During pregnancy, reduced vascular responses to constrictors contribute to decreased uterine and total vascular resistance. Thromboxane A(2) (TxA(2)) is a potent vasoconstrictor that exerts its ...actions via diverse signaling pathways, and its biosynthesis increases in preeclampsia. In this study, we hypothesized that maternal vascular responses to TxA(2) will be attenuated via Rho kinase, PKC, p38 MAPK, and ERK1/2 signaling pathways. Isolated ring segments of uterine and small mesenteric arteries from late pregnant (19-21 days) and virgin rats were suspended in a myograph, and isometric force was measured. Pregnancy did not affect uterine and mesenteric artery responses to the TxA(2) analog U-46619 (10(-9)-10(-5) M), but transduction signals associated with these contractions were different between pregnant and nonpregnant rats. Inhibition of Rho kinase (10(-6) M Y-27632) reduced sensitivity to U-46619 in virgin uterine vessels but did not inhibit these contractions in pregnant uterine arteries and had no effect on mesenteric vessels. Treatment of arterial segments with a PKC inhibitor (10(-6) M bisindolylmaleimide I) reduced U-46619-induced contractions in virgin uterine and mesenteric arteries and in pregnant mesenteric arteries. Pregnant uterine arteries, however, were unresponsive to PKC inhibition. Inhibition of ERK1/2 (10(-5) M PD-98059) and p38 MAPK (10(-5) M SB-203580) reduced U46619-induced contractions in nonpregnant vessels and in pregnant uterine and mesenteric vessels. These data suggest that normal pregnancy does not affect uterine and mesenteric contractile responses to TxA(2) but reduces the contribution of Rho kinase and PKC signaling pathways to these contractions in the uterine vasculature. In contrast, the role of ERK1/2 and p38 MAPK in U-46619-induced uterine contractions remains unchanged with pregnancy. TxA(2)-associated transduction signals and its regulators might present potential targets for the development of new treatments for preeclampsia and other pregnancy-associated vascular diseases.
Abstract
Exposure to ozone (O3) induces lung injury, pulmonary inflammation, and alters lipid metabolism. During tissue inflammation, specialized pro-resolving lipid mediators (SPMs) facilitate the ...resolution of inflammation. SPMs regulate the pulmonary immune response during infection and allergic asthma; however, the role of SPMs in O3-induced pulmonary injury and inflammation is unknown. We hypothesize that O3 exposure induces pulmonary inflammation by reducing SPMs. To evaluate this, male C57Bl/6J mice were exposed to filtered air (FA) or 1 ppm O3 for 3 h and necropsied 24 h after exposure. Pulmonary injury/inflammation was determined by bronchoalveolar lavage (BAL) differentials, protein, and lung tissue cytokine expression. SPMs were quantified by liquid chromatography tandem mass spectrometry and SPM receptors leukotriene B4 receptor 1 (BLT-1), formyl peptide receptor 2 (ALX/FPR2), chemokine-like receptor 1 (ChemR23), and SPM-generating enzyme (5-LOX and 12/15-LOX) expression were measured by real time PCR. 24 h post-O3 exposure, BAL PMNs and protein content were significantly increased compared to FA controls. O3-induced lung inflammation was associated with significant decreases in pulmonary SPM precursors (14-HDHA, 17-HDHA), the SPM PDX, and in pulmonary ALX/FPR2, ChemR23, and 12/15-LOX expression. Exogenous administration of 14-HDHA, 17-HDHA, and PDX 1 h prior to O3 exposure rescued pulmonary SPM precursors/SPMs, decreased proinflammatory cytokine and chemokine expression, and decreased BAL macrophages and PMNs. Taken together, these data indicate that O3-mediated SPM reductions may drive O3-induced pulmonary inflammation.
Aims
Detrusor underactivity (DU) is an understudied health concern with inadequate clinical management. The pathophysiology of DU is unclear, and current therapies fail to improve symptoms. The ...current studies characterized voiding function and contractility of bladder and urethral tissues in a novel rat model of DU.
Methods
Female obese prone (OP) and obese resistant (OR) rats were fed a 60 kcal% fat diet at 8 weeks old. A subset of rats (n = 4/strain) underwent uroflowmetry biweekly for 18 weeks in metabolic cages. At 40–56 weeks old, rats (n = 9–10/strain) underwent instrumented cystometry under urethane anesthesia. Following cystometry, bladder and urethral tissues (n = 8–9/strain) were harvested for in vitro assessments of contractility in response to carbachol, electric field stimulation, atropine, alpha, beta‐methylene ATP, and caffeine.
Results
OP rats exhibited increased urinary frequency (p = 0.0031), decreased voided volume (p = 0.0093), and urine flow rate (p = 0.0064) compared to OR rats during uroflowmetry. Bethanechol (10 mg/kg) did not alter uroflowmetry parameters. During cystometry, OP rats exhibited decreased bladder emptying efficiency (p < 0.0001), decreased pressure to generate a void (p < 0.0001), and increased EUS activity during filling (p = 0.0011). Bladder contractility was decreased in OP rats when exposed to carbachol (p < 0.0003) and ATP (p = 0.0004), whereas middle urethral contractility was increased when exposed to carbachol (p = 0.0014), EFS (p = 0.0289), and caffeine (p = 0.0031).
Conclusion
Impaired cholinergic and purinergic signaling in the bladder may contribute to poor voiding function in OP rats. In addition, increased urethral activity may engage a guarding reflex to augment continence and exacerbate incomplete emptying.
The main objective of these studies was to characterize metabolic, body composition, and cardiovascular responses to a free-choice high-fat, high-sucrose diet in female cycling and pregnant rats. In ...the nonpregnant state, female Sprague-Dawley rats offered a 3-wk free-choice high-fat, high-sucrose diet had greater energy intake, adiposity, serum leptin, and triglyceride concentrations compared with rats fed with standard chow and developed glucose intolerance. In addition, choice-diet-fed rats had larger cardiac ventricular weights, smaller kidney and pancreas weights, and higher blood pressure than chow-fed rats, but they did not exhibit resistance artery endothelial dysfunction. When the free-choice diet continued throughout pregnancy, rats remained hyperphagic, hyperleptinemic, and obese. Choice pregnant rats exhibited uterine artery endothelial dysfunction and had smaller fetuses compared with chow pregnant rats. Pregnancy normalized mean arterial blood pressure and pancreas weights in choice rats. These studies are the first to provide a comprehensive evaluation of free-choice high-fat, high-sucrose diet on metabolic and cardiovascular functions in female rats, extending the previous studies in males to female cycling and pregnant rodents. Free-choice diet may provide a new model of preconceptual maternal obesity to study the role of increased energy intake, individual food components, and preexisting maternal obesity on maternal and offspring physiological responses during pregnancy and after birth.
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