Regional heterogeneity in vascular contractile dysfunction in diabetic mice

Oxidative stress underlies many diabetic complications, including diabetic vasculopathy. It is unclear if oxidative stress has different effects in regionally distant arteries. We compared the contractile function of three arteries from diabetic mice and elucidated the mechanisms underlying their differential adaptation. We examined responses of the aorta, carotid and femoral arteries, isolated from the same diabetic (db/db) or normoglycemic control mice, to different vasoconstrictors in the presence and absence of indomethacin, apocynin, sulfaphenazole, L-NAME or a reactive oxygen species generating system to identify the enzyme(s) contributing to vascular dysfunction. Expression of superoxide dismutase (SOD) isoforms was measured. db/db aortae showed augmented contractile responses to KCl, phenylephrine, A23197 and U-46619 likely due to activated cyclooxygenases and hypersensitivity to thromboxane A2. Contractile responses of db/db carotid arteries were unaltered, likely due to higher SOD3 and SOD1 levels compared to the aortae. Femoral arteries were more vulnerable to oxidative stress, lacked SOD3 expression, and showed higher basal potassium channels activity. Phenylephrine contractions in femoral arteries were dependent on extracellular calcium entry; while contractions in aortae were dependent on extracellular calcium entry and intracellular calcium release. Femoral arteries from db/db mice exhibited higher basal potassium channels activity and attenuated contractility compared to control mice likely due to lower SOD levels. Heterogeneity exists between the three arteries at functional and molecular levels due to different signalling pathways and antioxidant defense mechanisms. Understanding regional differences in vasomotor control coupled with advanced delivery systems can help in developing therapies targeting specific vascular beds.