Exogenous estrogen use in male-to-female individuals has been linked to increased cardiovascular disease risk, though the mechanisms remain unclear. This study examines the effects of 17β-estradiol (E₂) on metabolic and aortic function in castrated (CAS) male Sprague Dawley rats. CAS rats received subcutaneous E₂ (CAS + E₂) or placebo (CAS + PL) pellets for ~35 days, with intact males serving as controls. Endothelium-dependent vasorelaxation (EDV) in response to acetylcholine and contractile responses to phenylephrine were measured in aorta before and after pharmacological inhibitors. Metabolic parameters and expression of proteins associated with vascular and insulin signaling were also determined in aorta and white adipose tissue (WAT). E₂ treatment reduced body weight, improved HbA1c and enhanced glucose tolerance in CAS rats compared to the CAS + PL group. Improved glucose homeostasis was associated with upregulation of estrogen receptor alpha, phosphorylated Akt/Akt, and glucose transporter-4 expression in WAT. However, E₂ increased plasma triglyceride and impaired EDV, indicating compromised vascular function. Our results suggest that impaired aortic relaxation in the CAS + E₂ group may be partly attributable to increased contractility. Additionally, we observed reduced G protein-coupled estrogen receptor and elevated inducible nitric oxide synthase expression, warranting further investigation into whether these factors contribute to the effects of E₂ on aortic relaxation.

Perivascular adipose tissue (PVAT) is a metabolically active adipose depot surrounding most blood vessels and contributes to vascular homeostasis through local regulation of vascular tone, inflammation, and metabolic signaling. In prediabetes and diabetes, PVAT may shift from a predominantly vasoprotective phenotype toward a pro-inflammatory and pro-contractile state characterized by reduced release of protective mediators and increased cytokine, reactive oxygen species, and vasoconstrictor signaling. Vascular injury may, in turn, further alter the PVAT phenotype, creating bidirectional adipose-vascular crosstalk that may contribute to disease progression. Biological sex, reproductive aging, and sex-hormone signaling appear to influence PVAT morphology, cellular composition, secretory function, and vascular effects, but the strength of this evidence varies substantially across species, vascular beds, and disease models. Unlike recent broad reviews of PVAT biology, this review examines PVAT across the prediabetes-to-diabetes continuum while recognizing that direct longitudinal evidence tracking PVAT between these metabolic states remains scarce. We critically evaluate the direct, indirect, and still-limited evidence for sex-specific PVAT mechanisms and integrate findings on immune-cell activity, adipokine and redox signaling, and vascular function across prediabetes, established diabetes, and related metabolic conditions. Defining these mechanisms may support the development of appropriately tested, sex-informed strategies for preventing and treating diabetes-associated vascular complications.