Functional status of microvascular vasomotion is impaired in spontaneously hypertensive rat

Abstract

Accumulating evidence demonstrates that microcirculation plays a role in the pathogenesis of hypertension. In the current study, we demonstrated that pancreatic islet microvascular vasomotion of spontaneously hypertensive rats (SHRs) lost the ability to regulate blood flow perfusion and exhibited a lower microvascular blood perfusion pattern which was negative correlated with blood glucose level. SHRs administrated with insulin revealed an improvement of pancreatic islet microvascular vasomotion and blood perfusion pattern. In vitro, the expressions of endothelial nitric oxide synthase (eNOS) and phospho-eNOSser1177 (p-eNOSser1177) were significantly decreased in high glucose exposed islet endothelial cells (iECs), accompanied with a higher ratio of eNOS monomer to eNOS dimer and a significantly increased malondialdehyde and nitrite levels. Meanwhile, barrier function, tube formation and migration capacities of high glucose exposed iECs were significantly inhibited. In contrast, iECs dysfunction induced by glucose toxicity and oxidative stress was attenuated or improved by supplement with insulin, L-arginine and β-mercaptoethanol. In summary, our findings suggest that functional status of pancreatic islet microvascular vasomotion is impaired in SHRs and provide evidence that treatment with insulin, L-arginine and β-mercaptoethanol improves endothelium-dependent microvascular vasomotion and meliorates iECs function due to anti-hyperglycemic and anti-oxidative effects, partly through mechanism involving regulation of eNOS and p-eNOSser1177.

New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

“…Similar observations were made in caveolin-1 depleted and angiotensin-II stimulated endothelial cells [141], in diabetic rats with improvement by nicorandil [142], in diabetic rats with improvement by green tea extract [143], in hypoxic pigs with improvement by L-citrulline [144], and in tachycardia/sympathetic over-activation in mice by isoproterenol [145]. eNOS dimer/monomer ratio was also decreased in diabetic db/db mice and normalized by saxagliptin [146], in erectile tissue of type 2 diabetes mellitus (T2DM) men [147], in mice with doxorubicin-induced cardiomyopathy and improvement by folic acid [148], in spontaneously hypertensive rats [149], and the improvement of eNOS coupling by increased eNOS dimer/monomer ratio by exercise training [150,151]. The critical role of this zinc-sulfur-complex for proper eNOS dimer formation was demonstrated by significant monomerization in a knock-in mouse expressing a C101A-eNOS mutant with impaired zinc-sulfur-complex forming ability [152].…”

Endothelial Nitric Oxide Suppresses Action-Potential-Like Transient Spikes and Vasospasm in Small Resistance Arteries

“…Vasomotion occurs in arteries from a wide range of species, including humans, and sustains organ and tissue function by optimizing blood flow. 1 – 3 It manifests as symmetrical, depolarizing oscillations of arterial smooth muscle membrane potential, underpinned by L-type voltage-gated calcium channel (VGCC) activity, that drives circa 0.05 to 0.2 Hz cycles of vasoconstriction/vasodilation. Vasomotion requires effective signaling cross-talk between arterial smooth muscle and endothelial cells and is abolished by compromised endothelial cell function, particularly the loss of NO-cGMP signaling.…”

Gene expression profiles of glucose toxicity‐exposed islet microvascular endothelial cells

“…Recently, we have reported that pancreatic islet microvascular vasomotion is impaired in the early stage of diabetes partially through the mechanism involving IMECs dysfunction induced by glucose toxicity and oxidative stress . Meanwhile, the protective effects of insulin administration are associated with its antihyperglycemic and antioxidative capacities on IMECs . Among the altered gene expression profiles induced by glucose toxicity, mRNAs and adaptive stress response signaling pathways are the important components.…”

“…11 Meanwhile, the protective effects of insulin administration are associated with its antihyperglycemic and antioxidative capacities on IMECs. 12 Among the altered gene expression profiles induced by glucose toxicity, mRNAs and adaptive stress response signaling pathways are the important components. And based on which, we speculate that a better understanding of the gene expression profiles of IMECs involved in glucose toxicity-induced dysfunction would help provide novel and more efficient therapeutic strategies for diabetes.…”