Uterine perivascular adipose tissue: A novel regulator of uterine artery hemodynamics during normal pregnancy

Introduction During pregnancy, uterine artery (UtA) blood flow increases compared to non-pregnant state, in part due to reductions in uterine artery tone. The main objective of this study was to determine the role of adipose tissue surrounding UtA (perivascular adipose tissue, PVAT) in pregnancy-induced changes in UtA blood flow and vasodilatory capacity. We hypothesized that uterine PVAT augments UtA blood flow and potentiates UtA dilatory responses in pregnant rats. Also, we hypothesized that pregnancy induces distinct changes in uterine PVAT morphology and gene expression as compared to other adipose depots. Methods Blood flow and vascular reactivity were measured in UtA in pregnant and non-pregnant rats using transonic perivascular probes and wire myography techniques, respectively. Reactivity to acetylcholine (ACh: induces endothelium-dependent relaxation, 10-9 - 3x10-5 M) and sodium nitroprusside (SNP: induces endothelium-independent relaxation, 10-11 - 3x10-5 M) was measured in isolated UtA in the presence and absence of PVAT-conditioned media (PVATmedia, 30-min incubation). Adipocyte size was determined in hematoxylin and eosin-stained sections of uterine PVAT and ovarian adipose tissue. Gene expression was determined in uterine and periaortic PVAT using qRT-PCR. Results Maximum and minimum uterine artery blood flow (UBF) were increased in UtA with intact PVAT compared to PVAT-denuded UtA from pregnant rats (UBFmax (mL/min); denuded: 1.47 ± 0.3 vs. intact: 2.23 ± 0.2, p = 0.01; UBFmin (mL/min); denuded: 0.71 ± 0.1 vs. intact: 1.16 ± 0.1, p = 0.0002). Uterine PVAT had no effect on UBF in non-pregnant rats (p [greater than] 0.9). UtA from pregnant and non-pregnant rats incubated with PVATmedia had reduced sensitivity to ACh compared to UtA controls (Pregnant, pEC50; -PVATmedia: 7.14 ± 0.1 vs. +PVATmedia: 6.38 ± 0.2, p = 0.0006; Non-pregnant, pEC50; -PVATmedia: 7.01 ± 0.1 vs. +PVATmedia: 6.50 ± 0.1, p = 0.005). PVATmedia had no effect on UtA sensitivity to SNP in either pregnant (p = 0.48) or non-pregnant rats (p = 0.2). Adipocyte area was greater in ovarian adipose tissue from pregnant compared to non-pregnant rats [Area (μm2/unit cell); Non-pregnant: 563.6 ± 76.6 vs. Pregnant: 857.6 ± 31.0, p = 0.02] but there were no group differences in uterine PVAT morphology (p = 0.6). Expression of uncoupling protein-1 (UCP-1) was downregulated (p = 0.02) in aortic PVAT but was unchanged in uterine PVAT (p = 0.4). Expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), adiponectin receptor (AdipoR1), and leptin were downregulated in uterine PVAT (p p [greater than] 0.6). Conclusions Uterine PVAT plays a regulatory role in uterine artery hemodynamics and reactivity during normal pregnancy and has a distinct and differential gene profile as compared to other perivascular depots. Ongoing studies investigate the effects of pregnancy on cross-talk between PVAT and maternal uterine arteries. Support or Funding Information University of North Texas Health Science Center Pilot Grant, CIHR (MOP142396) and the Women and Children's Health Research Institute at the University of Alberta