Biology subjects

La Favor, J. D.

Publications and source records attributed to La Favor, J. D..

4 recordsLinked to original sources

bioRxiv2025

Chronic administration of the hydrogen sulfide prodrug SG1002 partially protects against erectile dysfunction resulting from long-term androgen deprivation

AimsAndrogen deprivation therapy is a common treatment strategy for prostate cancer, although erectile dysfunction (ED) often coincides as an undesirable side-effect. Hydrogen sulfide (H2S) is an endogenous gasotransmitter with vasodilatory, anti-inflammatory, and antioxidant-like properties. H2S therapies are being developed for cardiovascular disease management, although the properties of H2S may also protect the erectile system. Materials and methods14-week-old male C57Bl/6 mice were subjected to sham surgery or castration, with castrated mice remaining untreated or treated orally with low- or high-doses of the H2S prodrug SG1002 over the five-week intervention. Erectile function was assessed by intracavernous pressure and mean arterial pressure during cavernous nerve stimulation. Vascular reactivity of the corpus cavernosum (CC), internal pudendal artery (IPA), and internal iliac artery (IIA) were assessed by dose-dependent responses to vasodilatory, vasocontractile, and neurogenic stimuli in myograph systems. CC contents of proteins related to cellular autophagy, antioxidant defense, and mitochondrial dynamics were assessed by immunoblotting. Fibrotic remodeling was assessed by Massons trichrome staining. Key findingsBoth doses of SG1002 provided an equivalent and moderate protection on erectile function against long-term androgen deprivation. Castration-induced alterations of several mechanisms of vasodilation and vasoconstriction of the CC and IPA were substantial, while alterations of the IIA modest, with subtle effects of SG1002 treatment across the vascular beds. SG1002 partially protected against castration-induced fibrotic remodeling of the IPA. SignificanceH2S therapy provides a modest but potentially clinically relevant protection of erectile function and health of the erectile structures against the harshly damaging effects of chronic androgen deprivation.

physiology↗

bioRxiv2025

Cystathionine γ Lyase Deletion Enhances Corpus Cavernosum Contraction via Thromboxane A2 and Neurogenic Pathways Without Affecting Endothelial Function

Cystathionine {gamma}-lyase (CSE) produces hydrogen sulfide (H2S), a vasodilator critical for vascular function. While its systemic effects are well-documented, its role in erectile physiology remains unclear. This study investigated the impact of CSE deletion on vascular and erectile tissue reactivity. We hypothesized that CSE knockout (CSE-KO) mice would exhibit endothelial dysfunction. A total of 22 CSE-KO and 22 age-matched wild-type (WT) controls were studied at one year of age. The internal iliac artery (IIA), internal pudendal artery (IPA), and corpus cavernosum (CC) were harvested for ex vivo functional assessments using tissue, wire, and pressure myography. Vasoconstriction was evaluated using phenylephrine, endothelin-1, U-46619, and electrical field stimulation (EFS). Endothelium-dependent relaxation was assessed using acetylcholine (ACh) and flow-mediated dilation, while endothelium-independent relaxation was evaluated using sodium nitroprusside (SNP). Sodium sulfide (Na2S) was used to assess H2S-mediated dilation. Non-adrenergic, non-cholinergic (NANC) transmission was evaluated using EFS. No significant differences were observed in ACh-, SNP-, or flow-mediated relaxation, although CSE-KO mice demonstrated impaired NANC-nerve mediated relaxation in the CC. Moreover, CSE-KO mice exhibited significantly enhanced CC contraction in response to U-46619 and EFS, suggesting increased vascular resistance in the end organ CC rather than the pre-penile arteries. Histological analysis revealed no significant structural or fibrotic remodeling in any tissue, although there was a trend toward increased collagen deposition in the IIA and IPA. These findings indicate that chronic CSE deficiency does not impair endothelial function but alters neurogenic control and increases vasoconstrictive sensitivity specifically in the CC, potentially predisposing to erectile dysfunction. NEW & NOTEWORTHYThis study highlights the critical role of hydrogen sulfide (H2S) in erectile physiology by demonstrating that CSE deletion does not impair endothelial function but significantly enhances neurogenic and thromboxane A2 receptor-induced vasoconstriction specifically in the corpus cavernosum (CC). These findings suggest that endogenous H2S modulates neurovascular control of erection. Its deficiency predisposes the erectile system to heightened vascular resistance predominantly in the end organ, providing novel insights into the vascular mechanisms underlying erectile dysfunction.

physiology↗

bioRxiv2025

Hydrogen sulfide protects erectile function through stimulation of antioxidant defense in the corpus cavernosum

Obesity is a major risk factor for erectile dysfunction, whereby excess reactive oxygen species (ROS) in the corpus cavernosum have been implicated as a causative factor. Hydrogen sulfide (H2S) is an endogenous gasotransmitter with vasodilatory and antioxidant properties. The objectives of this study were to determine the influence of H2S on erectile function, penile ROS, and expressions of endogenous antioxidant genes and proteins in the corpus cavernosum. These objectives were tested by 1) comparing wild type mice to mice deficient in cystathionine {gamma}-lyase (CSE-/-), a major endogenous source of H2S; and 2) by feeding wild type mice a control diet or high-fat, high-sucrose Western style diet (WD) for 18 weeks, with subgroups treated with and without the H2S prodrug SG1002 for the final 6 weeks of the dietary intervention. Erectile function was assessed by cavernous nerve-stimulated intracavernous pressure measurement, penile interstitial ROS was measured with a microdialysis approach, and cavernous gene and protein expression assessed by qRT-PCR and western blot, respectively. Erectile function was impaired in CSE-/- mice and following the WD, which was significantly improved in WD mice treated with SG1002. Penile ROS levels were increased in CSE-/- mice and following the WD, which were suppressed in WD mice treated with SG1002. The following genes were commonly decreased in CSE-/- mice and increased by SG1002 treatment: Nqo1, Gclc, Gstm1, Gpx1, Gpx4, Hmox1, Txnrd1, and Prdx3. Txnip was reciprocally increased in CSE-/- mice and decreased by SG1002 treatment. These data suggest that H2S positively influences erectile function and penile free radical balance, likely through augmentation of the glutathione and thioredoxin endogenous antioxidant systems.

physiology↗

bioRxiv2024

The Role of Sex in the Effects of Smoking and Nicotine in Cardiovascular Function, Atherosclerosis, and Inflammation

cigarette smoke (CS) invokes an inflammatory response involving increased levels of circulating cytokines and chemokines, vascular dysfunction, and atherosclerosis. The role of sex and nicotine in CS effects in cardiovascular function and atherosclerosis is unexplored. To assess the role of sex, male and female C57Bl/6 WT (wild type) and ApoE-/- mice were exposed to CS and nicotine for 16 weeks to bridge this literature gap. Heart rate and endothelial function were measured in the aorta of WT mice, while plasma levels of lipids, cytokines and chemokines and aortic plaque burden was assessed in ApoE-/- mice. CS increased heart rate to similar levels in both sexes and induced a stronger impairment in endothelial function in males and more plaque in females than nicotine. Females showed a higher necrotic core area at basal compared with males, while males had a higher calcification area than females by CS. Senescence-associated GLB1/-galactosidase (SA-GLB1) activity was elevated similarly in both sexes by both treatments. Total cholesterol (TC) was elevated by CS in both sexes. CS increased triglycerides (TG), very-low density lipoprotein (VLDL) and high-density lipoprotein (HDL) only in males and low-density lipoprotein (LDL) only in females. Interleukin 17A (IL17A) was upregulated by CS and nicotine in both sexes, while CS upregulated C-X-C motif chemokine ligand 5 (CXCL5/LIX) and interleukin 1 alpha (IL1A) in males and females, respectively. Additionally, nicotine metabolism showed sex specific responses to nicotine, but not smoking. Overall, we identified sex-specific pro-atherogenic responses to CS in the lipid profile, plaque area and composition and inflammatory markers. Males present a stronger impairment in endothelia dysfunction in WT mice, while females a stronger plaque burden in ApoE-/- mice exposed to CS. Elevated HDL and estrogens in males may offer partial protection against the harmful effects of CS. In contrast, elevated LDL and a pro-inflammatory state may promote a stronger pro-atherogenic phenotype in females exposed to CS.

cell biology↗