Temporal development of retinal arteriolar endothelial dysfunction in porcine type 1 diabetes

Abstract

Purpose: Although hyperglycemia is implicated in retinal vascular dysfunction associated with the development of diabetic retinopathy, the temporal influence of hyperglycemia on retinal arteriolar reactivity remains unclear. Development of a large animal model of diabetes relevant to the human retina for evaluation of vascular function is also lacking. Herein, we examined nitric oxide (NO)-mediated dilation and endothelin-1 (ET-1)-induced constriction in retinal arterioles at various time periods in a porcine model of type 1 diabetes.

Methods: Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2, 6, and 12 weeks of hyperglycemia, 427 ± 23 mg/dL) and age-matched control pigs (73 ± 4 mg/dL), and then cannulated and pressurized for vasoreactivity study using videomicroscopic techniques.

Results: Retinal arterioles isolated from control and diabetic pigs developed comparable levels of myogenic tone. The endothelium-dependent NO-mediated vasodilations to bradykinin and stepwise increases in luminal flow were significantly reduced within 2 weeks of hyperglycemia. The inhibitory effect was comparable following 6 and 12 weeks of hyperglycemia. However, the endothelium-independent vasodilation to sodium nitroprusside was unaffected. Constriction of retinal arterioles to ET-1 was unaltered at all time periods of hyperglycemia.

Conclusions: Our findings provide the first direct evidence for selective impairment of endothelium-dependent NO-mediated dilation of retinal arterioles within 2 weeks of hyperglycemia in a pig model of diabetes. By contrast, the ability of arteriolar smooth muscle to dilate to NO donor or contract to ET-1 was unaffected throughout the study period. This endothelial vasodilator dysfunction during early diabetes may contribute to development of retinopathy with chronic hyperglycemia.

Figure 1.

Vasodilator response of isolated and pressurized porcine retinal arterioles to bradykinin. Concentration-dependent vasodilation to bradykinin was significantly reduced in a similar manner following all three time periods of diabetes mellitus: (A) 2 weeks (control = 15 pigs; diabetes = 17 pigs), (B) 6 weeks (control = 4 pigs; diabetes = 5 pigs), and (C) 12 weeks (control = 4 pigs; diabetes = 9 pigs). *P < 0.05 versus control.

Figure 2.

Vasodilator response of isolated and pressurized porcine retinal arterioles to sodium nitroprusside. Concentration-dependent vasodilation to sodium nitroprusside was unaltered following all three time periods of diabetes mellitus: (A) 2 weeks (control and diabetes = 7 pigs each), (B) 6 weeks (control and diabetes = 4 pigs each), and (C) 12 weeks (control = 4 pigs; diabetes = 8 pigs).

Figure 3.

Vasodilator response of isolated and pressurized porcine retinal arterioles to increased flow. Dilation of retinal arterioles to a stepwise increase in pressure gradient (i.e., flow/shear stress) was significantly reduced following 2 weeks of diabetes mellitus (control and diabetes = 5 pigs each). *P < 0.05 versus control.

Figure 4.

Vasoconstrictor response of isolated and pressurized retinal arterioles to ET-1. Concentration-dependent vasoconstriction to ET-1 was unaltered following all three time periods of diabetes mellitus: (A) 2 weeks (control and diabetes = 6 pigs each), (B) 6 weeks (control and diabetes = 3 pigs each), and (C) 12 weeks (control and diabetes = 4 pigs each).