Comparison of Pulmonary and Systemic NO‐ and PGI₂‐Dependent Endothelial Function in Diabetic Mice

Abstract

Diabetes increases the risk of pulmonary hypertension and is associated with alterations in pulmonary vascular function. Still, it is not clear whether alterations in the phenotype of pulmonary endothelium induced by diabetes are distinct, as compared to peripheral endothelium. In the present work, we characterized differences between diabetic complications in the lung and aorta in db/db mice with advanced diabetes. Male, 20-week-old db/db mice displayed increased HbA1c and glucose concentration compatible with advanced diabetes. Diabetic lungs had signs of mild fibrosis, and pulmonary endothelium displayed significantly ultrastructural changes. In the isolated, perfused lung from db/db mice, filtration coefficient (Kf,c) and contractile response to TXA2 analogue were enhanced, while endothelial NO-dependent modulation of pulmonary response to hypoxic ventilation and cumulative production of NO2− were impaired, with no changes in immunostaining for eNOS expression. In turn, 6-keto-PGF1α release from the isolated lung from db/db mice was increased, as well as immunostaining of thrombomodulin (CD141). In contrast to the lung, NO-dependent, acetylcholine-induced vasodilation, ionophore-stimulated NO2− generation, and production of 6-keto-PGF1α were all impaired in aortic rings from db/db mice. Although eNOS immunostaining was not changed, that of CD141 was clearly lowered. Interestingly, diabetes-induced nitration of proteins in aorta was higher than that in the lungs. In summary, diabetes induced marked ultrastructural changes in pulmonary endothelium that were associated with the increased permeability of pulmonary microcirculation, impaired NO-dependent vascular function, with compensatory increase in PGI2 production, and increased CD141 expression. In contrast, endothelial dysfunction in the aorta was featured by impaired NO-, PGI2-dependent function and diminished CD141 expression.

Systemic Administration of Insulin Receptor Antagonist Results in Endothelial and Perivascular Adipose Tissue Dysfunction in Mice

“…On the other hand, S961 induced robust hyperglycemia and severe increase in HbA1c to the levels similar as in advanced-aged diabetic db/db mice [40,41], robust increase in GTT (much more pronounced than in the HFD model) and alterations in various RBCrelated indices including increased GSH/GSSH ratio in RBCs. Interestingly, the connection between diabetic erythropathy and endothelial dysfunction was suggested recently [42], and could be relevant in the context of the profound endothelial dysfunction in the S961treated animals.…”

Endothelial-mesenchymal transition induced by metastatic 4T1 breast cancer cells in pulmonary endothelium in aged mice

“…Importantly, the occurrence of EndMT in pulmonary circulation coincided with endothelial dysfunction in the aorta ( Figures 1 , 3 ), which are both associated with preserved and impaired NO-dependent function, respectively, underscoring the phenotypic heterogeneity of age-dependent changes in the aorta and pulmonary circulation. Interestingly, we recently observed phenotypic heterogeneity in systemic and pulmonary endothelium in response to diabetes ( Fedorowicz et al, 2018 ). Nevertheless, the co-occurrence of early-stage EndMT in the lungs and impaired endothelium-dependent vasodilation in TA and AA suggest that assessing age-dependent peripheral endothelial dysfunction may be of potential diagnostic and predictive value when evaluating the adverse response of the pulmonary endothelium to an insult resulting in EndMT.…”

Regulation of the Proliferation of Diabetic Vascular Endothelial Cells by Degrading Endothelial Cell Functional Genes with QKI‐7

“…It is usually regarded as the main regulator of blood vessels. When endothelial cells proliferate rapidly, the secretory expression of PGI2 will increase significantly [ 32 ]. In previous studies, researchers had found that in patients who have type 2 diabetes or atherosclerosis, the excessive proliferation of endothelial cells was associated with excessive secretion of PGI2.…”