Examining Sex Differences of Adipose Endothelial Cells and the Effects of Foxo1 Deletion

During obesity, adipose tissue undergoes significant remodeling to store excess energy. Adequate vascular growth is required for adipose expansion, which ensures proper oxygen and nutrient supply and prevents insulin resistance and metabolic disease. Thus, coordinated angiogenesis is critical for metabolic health during obesity. Transcriptomic analysis of adipose endothelial cells (ECs) from high-fat fed mice revealed that female ECs displayed a proliferative and chromatin-remodeled profile, while male ECs were enriched in inflammatory and senescence-associated signatures. Similar sex differences were observed in aging ECs. To assess the influence of sex hormones, a gonadectomy model was used. Surprisingly, the loss of gonadal hormones increased capillary density despite reduced levels of VEGFA in the adipose microenvironment. However, gonadectomy had no long-term effect on EC metabolism in culture, though direct estradiol stimulation did increase mitochondrial ATP production. One candidate contributor of sex differences is the endothelial quiescence-inducing transcription factor forkhead box O1 (FoxO1), which is more highly expressed in female ECs despite higher angiogenic activity. FoxO1 knockdown or inhibition in females led to a dysfunctional EC phenotype which was marked by inflammation, oxidative stress, impaired mitochondrial function, and DNA damage. These endothelial disturbances caused by FoxO1 loss were accompanied by lower capillary content in the females, a response not mirrored in males. Overall, these studies demonstrate that female ECs exhibit a healthier phenotype under obesogenic conditions, a trait that appears to be largely independent of sex hormones. Instead, FoxO1 emerges as a major contributor to this protective and resilient female endothelial profile.

Author dc:creator

• Pislaru, Alexandra

Advisor dc:contributor.advisor

• Haas, Tara

• Biology
• Physiology

Statement dc:rights

• Author owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.

Language dc:language

en

Handle dc:identifier.uri

https://hdl.handle.net/10315/43343

OAI identifier oai:identifier

oai:yorkspace.library.yorku.ca:10315/43343