(005) OBESITY IN EARLY-LIFE CAUSES LONG-TERM INFLAMMATION AND WNT SIGNALING PATHWAY DOWNREGULATION IN PUDENDAL ARTERIES OF YOUNG ADULT RATS: THE EARLY ONSET OF CELL SENESCENCE IN THE DEVELOPMENT OF ERECTILE DYSFUNCTION IN MALE RATS
Authors: Priviero F , Rodrigues Dos Passos R , Vieira Dos Santos C , Moura K , Townsend P , Tomazini Goncalves T , Wenceslau C , G Mccarthy C , Silva Carneiro F , Ceravolo G , Webb C 
Published: December 2024

Abstract

Introduction
Erectile dysfunction (ED) is largely associated with obesity, however, the consequences of early-life obesity for ED in young adulthood are unknown.

Objective
This study tested the hypothesis that obesity induced by preweaning overfeeding causes long-term metabolic damages that lead to inflammation, impaired vascular and erectile function, and affect blood pressure in young adult male rats (5-month-old).

Methods
At postnatal day (PND) 1, Wistar rats were divided into a normal litter (NL, 5 female +5 male pups/dam) or a small litter (SL, 2 male +1 female pup/dam) during lactation. After weaning, SL pups had increased body weight. Next, rats from both groups returned to normal size colonies (4-5 rats per cage) and were fed standard chow. At PND160, we evaluated body weight and fat pad deposition, mean arterial pressure (MAP) by tail-cuff, and pudendal artery (PA) and corpus cavernosum (CC) reactivity. Concentration-response curves to phenylephrine (PE) or acetylcholine (ACh) were performed in both preparations. In the CC both contraction and relaxation to electrical field stimulation (EFS) were obtained. Concentration-response curves were analyzed using non-linear regression analysis. A cytokine array was performed in plasma. RNA sequencing (RNAseq) analyses were performed in both PA and CC. Data was analyzed by Student’s t-test and presented as mean ± S.E.M. Statistical significance was set at p &lt; 0.05.

Results
At PND160 no differences in body weight were observed in SL (594 ± 14 g) compared to NL (559 ± 13 g), however, there was an increase in fat deposition in SL (retroperitoneal fat: NL 7.47 ± 0.69 g vs SL 11.25 ± 1.23 g; perigonadal fat: NL 10.05 ± 0.55 g vs SL 13.24 ± 1.16 g). MAP was higher in SL (120.5 ± 1.20 mmHg vs 114.9 ± 0.58 NL). In the PA, ACh-induced relaxation was reduced in SL (Emax: 28 ± 6%) vs NL (Emax: 68 ± 5.5%), with no changes in the contraction to PE. In the CC, EFS-induced relaxation was significantly decreased in SL rats compared to NL rats (16 Hz: NL 3.06 ± 0.28% vs SL 2.39 ± 0.53%). The cytokine array demonstrated increased plasma levels of pro-inflammatory cytokines associated with metabolic dysfunction and aging, including CCL5, Lipocalin, MCP-1, CX3CL1, and MMP2. RNAseq revealed that in PA from SL rats, 289 and 224 genes were down and upregulated, respectively, while in the CC from SL rats, 115 genes were downregulated, and 110 genes were upregulated. Among them, the hcn2 gene (which encodes HCN2, the hyperpolarization-activated cyclic nucleotide-gated potassium and sodium channel 2) was strongly downregulated in both PA and CC, which may affect mechanotransduction. In addition, enriched gene ontology revealed the downregulation of the Wnt signaling pathway in PA, which is associated with the early onset of cell senescence.

Conclusions
Our data shows that, in rats, early-life obesity has long-term consequences leading to endothelial and cavernosal dysfunction observed in young adulthood and this might be linked to metabolic dysfunction, inflammation, and premature cell senescence.

Disclosure
No.