Obesity is a well-established risk factor for erectile dysfunction (ED); however, the long-term vascular consequences of early-life obesity on corpus cavernosum (CC) and pudendal artery (PA) function remain unclear. We hypothesized that early overnutrition promotes cellular senescence and tissue remodeling, impairing cavernosal and pudendal function in adulthood. Methods: Male Wistar rats were assigned at birth to small litter (SL; 3 pups/dam) to induce early overnutrition, or to normal litter (NL; 10 pups/dam). Both groups were weaned on postnatal day (PND) 21 and maintained on standard chow until PND160. Body weight, fat pad mass, and systolic blood pressure (SBP) were recorded. Functional reactivity was assessed in the CC and PA via responses to phenylephrine (PE), acetylcholine (ACh), and electrical field stimulation (EFS). RNA sequencing (RNA-seq) and RT-qPCR were performed to evaluate gene expression associated with senescence and remodeling. Results: Despite no differences in final body mass, SL rats exhibited increased retroperitoneal and perigonadal fat, along with elevated SBP (SL-120.5±1.20mmHg x NL-114.9±0.58mmHg). In the CC, EFS-induced relaxation was reduced in SL rats (16Hz: 2.39 ± 0.53mN x NL: 3.06 ± 0.28mN), while PE and EFS-induced contractions were enhanced and attenuated by indomethacin, suggesting prostanoid involvement. In the PA, ACh-induced relaxation was significantly impaired in SL rats (Emax: SL 28 ± 6% x NL 68 ± 5.5%), without changes in PE responses. RNA-seq revealed 124 differentially expressed genes (DEG’s) in the CC, and 99 DEG’s in the PA. Enrichment analysis shows significant involvement of pathways related to tissue remodeling and metabolic regulation, including fibrosis-associated genes (Col1a1, Fstl3, Adamts6, Thbs6), as well as key metabolic signaling cascades such as PI3K-Akt-mTOR and secretin GPCRs family. In the CC, RT-qPCR confirmed increased expression of Bgn and Col1a2, indicative of extracellular matrix remodeling, along with elevated Calcrl and reduced Vipr2 and Glp1/2r, supporting senescence-driven tissue remodeling. Conclusions: Early-life obesity is associated with long-term structural and functional impairments in the CC and PA, likely contributing to erectile dysfunction in adulthood. These findings suggest that early metabolic insults may drive senescence and fibrosis through secretin GPCR signaling. Ongoing studies aim to further clarify the metabolic and mechanistic links to erectile dysfunction.
Gonçalves et al. (Mon,) studied this question.