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Obstructive sleep apnea (OSA) is characterized by loss of airway patency during sleep. OSA prevalence in obese patients is approximately double that of normal weight patients, as noted in humans, rats, pigs, and brachycephalic dogs. Leptin is normally transported from the periphery across the blood brain barrier (BBB) where it acts in the central nervous system (CNS) to activate ion channels in neurons. Peripheral hyperleptinemia associated with obesity saturates and downregulates leptin transport proteins at the BBB leading to a state of relative leptin deficiency in the CNS. This relative deficiency may be partially responsible for OSA because, regardless of weight, OSA patients have plasma leptin levels 50% higher than controls, with disease severity proportional to the degree of hyperleptinemia. Thus, we hypothesize that dysregulated leptin signaling in the CNS may contribute to loss of tongue muscle tone via ion channels dysfunction in the hypoglossal motoneurons (XII MNs) that innervate the tongue. To test our hypothesis that disrupted leptin signaling contributes to the loss of XII MN activity, we fed 12 male and 12 female CD1 mice and litter-matched controls a high-fat diet (HFD) for 16 weeks starting at 3-5 weeks old. Mice fed a HFD gained more weight than control mice (M: 45±12 vs 27±7 g, F: 34±18 vs 22±12 g, HFD vs control, p < 0.05), had increased visceral fat pad mass (M: 8±5 vs 3±2 g, F: 12±5 vs 3±2 g, HFD vs control, p < 0.05) and were more likely to have hepatic lipidosis (M: 10/11 vs 0/12, F: 8/11 vs 0/12, HFD vs control, p < 0.05). Surprisingly, male fed a HFD did not have significantly increased serum leptin levels compared to controls (8301±4053 vs 4392±3408 pg/ml, p > 0.05), while female fed a HFD did (7504±5327 vs 2842±4277 pg/ml, p < 0.05). Obesity is also associated with increased inflammation, thus serum inflammatory markers TNFα (M: 13±7 vs 9±7 pg/ml, F: 16±9 vs 10±7 pg/ml, p < 0.05) as well as IL-6 (M: 152±122 vs 65±34 pg/ml, F: 143±122 vs 57±25 pg/ml, p < 0.05) were significantly higher in HFD compared to control mice. RNA sequencing from 10 HFD and 10 control brainstem slices containing XII MNs uncovered significant (p < 0.1) upregulation of 6 genes and downregulation of 9 genes including DnaJ heat shock protein family member B12 (Dnajb1), nuclear paraspeckle assembly transcript 1 (Neat1), ankyrin 2 (Ank2), low density lipoprotein receptor-related protein (Lrp1), and ryanodine receptor (RyR2). These genetic changes suggest disrupted ion channel function as well as neuronal stress. Future research will evaluate the functional effects of these genetic changes to elucidate mechanistic links between obesity, leptin signaling and OSA onset. Midwestern University One Health Grant Student Award (Myers), Midwestern University One Health Grant Faculty Award (Vallejo, Revill, Bussey), Boehringer Ingelheim Veterinary Scholars Program (Myers) 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.

Alzheimer’s disease (AD) is the most common form of dementia and among the leading mortalities in the US. There is growing evidence supporting a connection between AD and cardiovascular disease (CVD). Variant isoforms of apolipoprotein E (APOE) are risk factors for AD and CVD. Compared to the most common APOE isoform, APOE3 (E3), APOE4 (E4) increases AD risk. In order to study APOE-mediated processes, posterior cerebral arteries (PCA) and common carotid arteries (CCA) were isolated from mice expressing human-ApoE targeted replacement of APOE3 (B6.129P2- Apoetm2(APOE*3)Mae N8) and APOE4 (B6.129P2- Apoetm3(APOE*4)Mae N8)(Taconic Labs). Our objective was to determine whether the E3 and E4 allele cause different mechanical properties in the absence of extracellular Ca2+ in the PCA and CCA isolated from young (Y, 3-4mo), adult (Ad, 12-15mo), and aged (Ag, 18-22mo), homozygous E3 and E4, male and female mice. We hypothesized that E4 would alter PCA and CCA structure/function when compared to age matched E3 cohorts. 5-8mm segments of PCA and CCA were isolated, cleaned of connective tissue, cannulated, and placed into an arteriograph. Upon equilibration, all vessels were challenged with 60mM [K+] to assess viability. Vessels not responding to 60mM [K+] were discarded. Mechanical characteristics, including lumen diameter (LD), wall thickness (WT), passive distensibility (PD), and stress/strain (S/S) were measured at intraluminal pressures ranging from 10-140mmHg. We observed no statistical differences in LD, PD, or S/S in PCAs and CCAs of Y and Ad, E3 and E4 mice. For LD and WT, Ag E3 was greater than Ag E4 (p ABRC/ADHS18-205211 (JVE, TBJ, CBJ, DME), Arizona Alzheimer's Consortium (funded by the Arizona Department of Health Services, Contract No. CTR040636) and matching funds from Midwestern University (DME), Biomedical Sciences Program (BG, LJS, DME), Biomedical Sciences Start-up Funds (DME). LJS and ASH equally contributed as first authors. 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.

Alzheimer’s disease (AD) is the most common form of dementia and is the 6th leading cause of death in the US. Growing evidence supports a link between AD and cardiovascular disease (CVD). Variant isoforms of apolipoprotein E (APOE) are risk factors for both AD and CVD. The most common APOE isoform, APOE3, has neutral risk for developing AD, whereas APOE4 increases AD risk. Pathogenic alterations in cardiac- and carotid- artery function are known to contribute to neurodegenerative diseases including AD. In this aging study we characterize cerebrovascular, aortic and cardiac function in the young (3–4-month-old), and aged (18-20-month-old) mice expressing human-ApoE targeted replacement of APOE3 (B6.129P2-Apoetm2(APOE*3)MaeN8) and APOE4 (B6.129P2-Apoetm3(APOE*4)MaeN8) (Taconic Labs). In vivo high-resolution ultrasound imaging was performed to evaluate the structure and function of the heart, aorta, carotid artery (CA), and posterior cerebral artery (PCA) blood flow in young, and aged hAPOE3 and hAPOE4 mice. Results were considered significant at p ABRC/ADHS18-205211 (DME, CBJ), Arizona Alzheimer's Consortium (funded by the Arizona Department of Health Services, Contract No. CTR040636) and matching funds from Midwestern University (DME), Biomedical Sciences Program (JF, KW, JD, DME), Biomedical Sciences Start-up Funds (DME) 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.

Regular low-impact physical activity is generally allowed in patients with Marfan syndrome, a connective tissue disorder caused by heterozygous mutations in the fibrillin-1 gene. However, being above average in height encourages young adults with this syndrome to engage in high-intensity contact sports, which unfortunately increases the risk for aortic aneurysm and rupture, the leading cause of death in Marfan syndrome. In this study, we investigated the effects of voluntary (cage-wheel) or forced (treadmill) aerobic exercise at different intensities on aortic function and structure in a mouse model of Marfan syndrome. Four-week-old Marfan and wild-type mice were subjected to voluntary and forced exercise regimens or sedentary lifestyle for 5 mo. Thoracic aortic tissue was isolated and subjected to structural and functional studies. Our data showed that exercise improved aortic wall structure and function in Marfan mice and that the beneficial effect was biphasic, with an optimum at low intensity exercise (55–65% V̇o2max) and tapering off at a higher intensity of exercise (85% V̇o2max). The mechanism underlying the reduced elastin fragmentation in Marfan mice involved reduction of the expression of matrix metalloproteinases 2 and 9 within the aortic wall. These findings present the first evidence of potential beneficial effects of mild exercise on the structural integrity of the aortic wall in Marfan syndrome associated aneurysm. Our finding that moderate, but not strenuous, exercise protects aortic structure and function in a mouse model of Marfan syndrome could have important implications for the medical care of young Marfan patients. NEW & NOTEWORTHY The present study provides conclusive scientific evidence that daily exercise can improve aortic health in a mouse model of Marfan syndrome associated aortic aneurysm, and it establishes the threshold for the exercise intensity beyond which exercise may not be as protective. These findings establish a platform for a new focus on promoting regular exercise in Marfan patients at an optimum intensity and create a paradigm shift in clinical care of Marfan patients suffering from aortic aneurysm complications.