Delineating Mechanisms of Impaired Vasoreactivity in Thermoneutrality

Cardiovascular disease (CVD) has a devastating impact on Veteran health and is a leading cause of both hospitalization and death. Early pathology of CVD is characterized by impaired vasoreactivity (constriction and dilation). As the vasculature serves the critical functions of distributing nutrients and regulating blood pressure, it is important to target early dysfunction in the vascular to further understand and prevent this chronic pathology. We recently housed rats at thermoneutral (TN) conditions and observed debilitated vasoreactivity along with high blood pressure in females, resulting in an animal model well-suited to further CVD investigation along with sex differences in pathology. Perivascular adipose tissue (PVAT), considered brown adipose tissue (BAT), surrounds and regulates the vasculature. Remodeling of PVAT, or the change in PVAT phenotype from BAT to white adipose tissue (WAT), may cause dysfunction in PVAT’s paracrine signaling to the vessel. In a preliminary study, we housed rats at either room temperature (RT) or TN and investigated their own PVAT or PVAT from the oppositely- housed animals along with each rat’s own aorta for vasoreactivity ex situ. In aorta of TN-housed animals analyzed with PVAT from RT-housed animals, the vessels showed a significant increase in vasodilation capacity, strongly suggesting that PVAT not only regulates vasoreactivity, but can repair consistently observed TN-induced diminished dilation. We hypothesize that PVAT whitening results in diminished paracrine signaling mechanisms to the vasculature, causing damaged vasoreactivity. Furthermore, sex as a biological variable determines the pathology of diminished PVAT and vasculature crosstalk. We will determine whether dysfunction in vascular tissue is governed by altered PVAT paracrine signaling associated with PVAT whitening, define the impact of estrogen on PVAT whitening and vascular dysfunction, and elucidate whether PVAT remodeling drives altered β-adrenergic- induced response to temperature. Experimental results supporting these aims will not only generate novel data on TN-induced PVAT regulation of vasculature and mitochondrial metabolism in female and male rats, but also pinpoint sex differences in treatment modalities for impaired vascular function in all Veterans with CVD.