In Vivo Targeting of the Endothelium to Improve Vascular Function in a Rodent Model of Type 2 Diabetes

Abstract

Endothelial dysfunction has been identified as an early event in the progression of cardiovascular complications (e.g. hypertension, cardiomyopathy, stroke) commonly observed in patients with Type 2 Diabetes (T2D). Importantly, reduction/reversal of endothelial dysfunction is expected to mitigate the cardiovascular deficits associated with T2D. Small‐ and intermediate‐conductance, Ca2+‐activated K+ channels (KCa2.3 and KCa3.1, respectively) are prominently expressed in the vascular endothelium, and pharmacologic activators of these channels (e.g. SKA‐31) induce robust vasodilation upon acute exposure in isolated arteries and intact animals. However, the effects of prolonged in vivo administration of KCa activators such as SKA‐31 have not been examined to date. In our current study, we have hypothesized that daily administration of SKA‐31 (10 and 30 mg/kg, I.P. injection) to male, Type 2 Diabetic Goto‐Kakizaki rats (T2D GK, 14 weeks of age) for 12 weeks would ameliorate diabetes‐related cardiovascular deficits. In isolated mesenteric resistance arteries examined by pressure myography, we observed that SKA‐31 treatment significantly improved endothelium‐dependent vasodilation in response to 0.3 μM acetylcholine (ACh) (percent of maximal dilation = 37.7 ± 7.3% and 33.6 ± 6.2% for 10 and 30 mg/kg treatments) compared with vehicle‐treated animals (20.7 ± 3.1%) (means ± S.D., n = 6 animals/group). Similar effects were observed for 0.3 μM bradykinin (BK) (evoked vasodilation = 54.1 ±7.8% and 47.9 ± 6.6% for 10 and 30 mg/kg SKA‐31, respectively) compared with vehicle (33.6 ±6.1%). SKA‐31 administration also reduced alpha1‐adrenergic (phenylephrine, 1 μM) stimulated constriction in 10 and 30 mg/kg treated T2D GK rats (percent of maximal contraction = 37.1 ± 5.0% and 36.1 ± 3.7%, respectively) compared with vehicle treated animals (46.6 ± 4.5%, n = 6 per group). Western blot analyses further revealed that SKA‐31 administration increased the expression of mesenteric KCa2.3 and KCa3.1 channels and associated cell‐signaling components (i.e. type 1 IP3 receptor and the SERCA2 Ca2+‐ATPase) that contribute to endothelium‐dependent, agonist‐evoked vasodilation. In contrast, SKA‐31 treatment did not augment ACh and BK evoked vasodilation in myogenically active, cremaster skeletal muscle resistance arteries from the same animals, compared with the vehicle treated group. Collectively, these data demonstrate that in vivo administration of an endothelial KCa channel activator can selectively improve vascular function in the setting of T2D.Support or Funding InformationThis study was supported by research funding to APB from the Canadian Institutes of Health Research (MOP‐142467) and the Natural Sciences and Engineering Research Council of Canada (RGPIN‐2017‐04116), and to HW from the National Institutes of Health (R21 NS101876).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.