Sex differences in Mesenteric Arterial Function at Pre-Diabetic and Diabetic Stage of UC Davis Type 2 Diabetic Mellitus Rats

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UC Davis type 2 diabetes mellitus (UCD-T2DM) rat is a validated model of type 2 diabetes exhibiting etiology very similar to clinical T2DM seen in humans compared to other rodent models. It is characterized by polygenic adult-onset obesity and diabetes observed in both sexes along with development of insulin resistance, impaired glucose tolerance, and subsequent β-cell decompensation. The objectives of this study were to investigate whether 1) the mesenteric arterial function is impaired and 2) sex differences exist in the development of abnormal vascular responses in UCD-T2DM rats at pre- diabetic and diabetic stage. Endothelium-dependent vasodilation (EDV) to acetylcholine (ACh, 10−8 to 10−5 M) was measured in mesenteric arteries (MA) pre-contracted with phenylephrine (PE, 2 μM). Concentration response curves (CRC) to sodium nitroprusside (SNP) (Nitric oxide (NO) donor, 10−9 to 10−5 M) and contractile agents such as PE (10−7 to 3×10−5 M) or endothelin-1 (ET-1, 10−10 to 10−7 M) were also determined. ACh-induced relaxation was significantly impaired in MA of pre-diabetic and diabetic rats, regardless of sex. However, in pre-diabetic stage, the extent of impairment was greater in males compared to that of female rats. When animals become diabetic, MA from female rats demonstrated a greater suppression of EDV than that of males. Similar to ACh responses, the relaxation responses to NO donor (SNP) were also impaired in MA of pre-diabetic and diabetic rats, in both sexes. Furthermore, female diabetic rats exhibited more impairment compared to male diabetic. In addition, arteries from female diabetic but not male diabetic showed a larger shift of SNP CRC to the right compared to their respective pre-diabetic animals. Finally, the sensitivity of MA to contractile agents such as PE and ET-1 was significantly enhanced in female diabetic rats compared to other groups. Our data, for the first time, show that the mesenteric arterial function of UCD-T2DM rats is impaired in both sexes as early as pre-diabetic stage. Moreover, we demonstrated a greater predisposition of MA to vascular injury in female diabetic rats, might be due to an altered sensitivity of arteries to contractile agents and NO. Support or Funding Information. Supported by NIH/NIHLBI.