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Impact of Acute and Chronic Hyperglycemia on Vasoconstrictor Responses of Retinal Venules: Role of Reverse-Mode Sodium-Calcium Exchanger
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Hyperglycemia, a hallmark of diabetes, is associated with increased retinal fluid filtration, a process heavily influenced by the postcapillary pressure and venous constriction. In hyperglycemia/diabetes, the serum level of vasoconstrictors endothelin-1 (ET-1) and thromboxane A2 (Ca^2^+) are elevated, and ET-1 has been implicated in retinal venous pathologies such as diabetic retinopathy and retinal vein occlusion. However, their impacts and mechanistic actions on venular vasomotor activity in the retina with hyperglycemic/diabetic insult remain unclear. First, we characterized the mechanistic action of ET-1 on isolated porcine retinal venules by examining the roles of ET-1 receptors, extracellular calcium (Ca^2^+) L-type voltage-operated calcium channels (L-VOCCs), Rho kinase (ROCK), and protein kinase C (PKC) in ET-1-induced vasoconstriction. We found that extracellular Ca^2^+ entry via L-VOCCs is essential for developing and maintaining basal tone of porcine retinal venules. ET-1 causes significant constriction of retinal venules by activating endothelin A receptors (ETvARs) and extracellular Ca^2^+ entry independent of L-VOCCs. Activation of ROCK signaling, without involvement of PKC, appears to mediate venular constriction to ET-1 in the porcine retina. Second, we found that chronic hyperglycemia (diabetes) and acute hyperglycemia (incubating the vessels with 25 mM glucose for 2 hours) significantly enhanced retinal venular constriction to ET-1, norepinephrine, and TXAv2 analogue U46619. Angiotensin II and phenylephrine elicited insignificant constriction of retinal venules. Moreover, the receptor mRNA expressions for ET-1, TXAv2, and αv2vA-adrenoceptor were not altered in diabetic venules, but the ET-1 level in vitreous humor was elevated in diabetic animals. After exposure to a high glucose (25 mM), the isolated human retinal arterioles also exhibited enhanced constriction to ET-1. Administration of both reverse-mode sodium-calcium exchanger (NCX) inhibitor KB-R7943 and sodium hydrogen exchanger (NHE) blocker cariporide did not affect the vasoconstriction to ET-1 in normal vessels but abolished the enhanced constriction to ET-1 in diabetic venules. Overall, our findings indicate that both chronic and acute hyperglycemia augment constriction of retinal venules to ET-1, U46619, and norepinephrine, via activation of both reverse-mode NCX and NHE. It is speculated that the enhanced venular response to these vasoconstrictors may increase capillary filtration by elevating postcapillary venular pressure during the early stage of diabetes. These pathophysiological changes may consequently promote tissue edema and development of diabetic retinopathy, in addition to the reduction of ocular perfusion. Blockade of reverse-mode NCX and NHE in retinal venules might provide a new therapeutic strategy to mitigate the diabetes-induced impairment of retinal microvascular function.
Chen, Yen-Lin (2019). Impact of Acute and Chronic Hyperglycemia on Vasoconstrictor Responses of Retinal Venules: Role of Reverse-Mode Sodium-Calcium Exchanger. Doctoral dissertation, Texas A&M University. Available electronically from