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The opioid overdose and opioid use disorder (OUD) epidemics are concomitant with nearly a 2-fold increased risk of cardiovascular disease (CVD). Opioid abuse during pregnancy increases the incidence of neonatal opioid withdrawal syndrome (NOWS) by 5-fold; however, the long-term effects on the offspring’s cardiovascular health are understudied. Previously, we have shown that both male and female offspring from dams exposed to mu-opioid receptor agonist morphine (MOR) during pregnancy display high blood pressure and reduced renal function as adults. Further, cardiovascular tissues of MOR-exposed offspring show downregulation of the endogenous opioid peptide proenkephalin (PENK) mRNA expression, which has been shown to play a role in modulating the adrenergic receptors signaling. This study aimed to investigate whether increased blood pressure in MOR-exposed offspring is associated with the activation of the sympathetic system.Sprague Dawley dams were treated with escalating doses of MOR (5-20 mg/kg/day, s.c) or saline (VEH) from gestational day 1 to 18. At 16 weeks, rats were implanted with femoral artery catheters for direct blood pressure measurements in response to the alpha-adrenergic receptor (A-ADR) blocker doxazosin (4 mg/kg/day, s.c) or saline. At the end of the study, plasma norepinephrine (NE) was measured by HPLC, and brain micropunches of the paraventricular nucleus of the hypothalamus (PVN), implicated in blood pressure regulation, were collected for RNAseq analysis.MOR-exposed offspring showed a greater reduction in the pressor response to mecamylamine (5 mg/kg, IP, delta change in mmHg: F-MOR -44.9±5.8 vs F-VEH -18.3±1.3, p0.05, n=6-8). Renal mRNA expression of the alpha-adrenergic receptor was downregulated ~3-fold (-2ddCt n=6-8, p HL135158 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Opioid use disorder (OUD) is one of the greatest public health threats in the US. In 2020, more than 69,000 Americans died of a drug overdose involving opioids. Starting in 2014, an alarming third wave is on the rise now caused by synthetic opioids, specifically illicit fentanyl (FEN). OUD among pregnant women is an understudied area related to the opioid epidemic, showing a 5-fold increase incidence of neonatal opioid withdrawal syndrome (NOWS). Currently, the only two FDA-approved medications indicated for medication assisted treatment (MAT) during pregnancy are methadone and buprenorphine. While some general guidelines have been established to place pregnant woman on MAT, the misuse of fentanyl has challenged the current pharmacotherapies, urging for the characterization of pre-clinical models.The aim of this study was to investigate the trasngenerational effects of opioids on the cardiovascular system. We subjected female rats to opioids exposure during pregnancy. We investigated: 1) In the newborns, the morphometrics and withdrawal symptoms; 2) In the adult offspring, the locomotor sensitization 3) The short and long-term plasma endogenous opioids peptides status, and 4) the transcriptomics of brain areas involved in the neural interface between motivation and action.We found that female and male neonates from opioids-treated dams are smaller through the lifespan compared to VEH-exposed counterparts (n=6, p This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

We have shown that male mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display increased blood pressure and sympathetic activation compared to controls (C) when fed a high fat diet (HF). Obese MSEW males also show exacerbated pressor response to the acute stimulation of epididymal white adipose tissue (eWAT) with capsaicin, a transient receptor potential cation channel subfamily V member 1 (TrpV1) ligand. Further, selective afferent denervation reduces blood pressure in MSEW mice only. We also reported that increases in serotonin (5-HT) levels in eWAT could serve as a potential endogenous factor stimulating sensory neurons. The goal of this study was to identify whether MSEW induces changes in the transcriptomes of eWAT and dorsal root ganglia (DRG) that could be associated with sensory neuron stimulation. In addition, we investigated MSEW-induced changes in lipid class and kinases activity. After weaning, C57BL/6J male C and MSEW pups (n=4/group) were placed on HF (60% Kcal from fat) for 16 weeks. Then, mice were euthanized and eWAT and DRGs were collected for tissue analysis. Pamstation12 instrument (PamGene International, Netherlands) was used for kinase activity profiles. For lipidomic analysis, lipids were extracted using acidified organic solvents, and dry residues were reconstituted for analysis using a Shimadzu Nexera UHPLC system coupled with an AB Sciex 6500+ Q-Trap linear ion trap/triple quadrupole mass spectrometer. RNA-sequencing was performed by Novogene Corp Inc.Overall, MSEW decreased the phosphorylation of ~20 kinases in eWAT (e.g. AKT, SGK, PKA, PKG, JNK, PAKA, ERK, AMPK), while increasing phosphatidylglycerols (PG) in eWAT (p HL135158 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Increased levels of pro-inflammatory cytokine Interleukin 17a (IL17) from adipose tissue have been linked to hypertension and metabolic syndrome in both humans and mice. Studies have demonstrated a causal role for IL17 in vascular dysfunction in angiotensin II-induced hypertension. IL17 secretion is modulated by T-helper 17 (Th17) lymphocytes downstream of mineralocorticoid receptor (MR) activation on dendritic cells (DC). In models of obesity, Th17 are known to infiltrate and expand in adipose tissue (AT). Perivascular AT (PVAT) directly modulates vascular function via secretion of adipose-derived factors. Previously, we have shown that female mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, display exacerbated obesogenic response to high fat diet feeding (HF) and metabolic syndrome-like phenotype that can be attenuated by the chronic treatment with MR antagonist spironolactone. Therefore, this study aimed to determine if there is an MR-dependent role of IL17 from PVAT on endothelial function in obese female MSEW mice. Female MSEW and control (C) mice were weaned onto HF (60 % Kcal from fat) for 20 weeks, then randomized to receive either vehicle (50% Ora swift in drinking water) or spironolactone (100 mg/kg/d in vehicle) treatment for 2 weeks. Upon euthanasia, plasma was to measure cytokines using a milliplex assay (n=5 per group). Thoracic aortas were then isolated and cleaned for vascular reactivity studies, and aortic and mesenteric perivascular adipose tissue (aPVAT and mPVAT, respectively) was collected in DMEM (2% BSA, 2-hour incubation, 37C). Cumulative concentration response (CCR) curves were performed for acetylcholine (Ach, 10-5 to 10-9 M) and sodium nitroprusside (SNP, 1x10-6 to 1x10-14 M) after pre-constriction with serotonin (2×10-3 M, 5 ul). Maximal vascular relaxation of aortic rings was similar between groups, however, preincubation with mPVAT media explant impaired vascular relaxation only in MSEW mice (p HL135158 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.