Summary Type I interferon (IFN) medications cause various adverse reactions, including vascular diseases. Although an association between chemokines and vascular diseases has also been reported, the relationship between type I IFN and chemokines in vascular endothelial cells (VEC) remains unclear. To provide clues to pathogenesis of the diseases, we analysed the effects of type I IFN on chemokine production in human VEC. Type I IFN induced higher CX3CL1 (fractalkine) mRNA expression and protein secretion in pulmonary arterial VEC than in umbilical vein VEC. Type I IFN also induced CCL5 [regulated upon activation normal T cell expressed and secreted (RANTES)] production in VEC, especially in lung micro‐VEC. IFN‐β induced much higher chemokine production than IFN‐α, and Janus protein tyrosine kinase (JAK) inhibitor I prevented type I IFN‐induced chemokine secretion. Type I IFN‐induced chemokines may be involved in the pathophysiology of pulmonary vascular diseases, and the JAK inhibitor may serve as a therapeutic option for these diseases.

Although microvascular cell death is a well established hallmark of diabetic retinopathy, which is a major cause of vision loss, much remains to be learned about the functional changes that precede the onset of morphological damage to retinal blood vessels. Early alterations of function are of interest since they may contribute to the development of irreversible pathological events. Because one of the earliest retinal effects of diabetes is the dysregulation of blood flow, we asked whether diabetes alters the functional organization of the capillary/arteriolar complex, which is the operational unit that plays an important role in regulating local perfusion. In this study, the effect of diabetes on the electrotonic architecture of the retinal microvasculature was characterized. To do this, we quantified the efficacy by which voltages are transmitted between pairs perforated-patch pipettes sealed onto abluminal cells located at well defined locations in capillary/arteriolar complexes freshly isolated from the retinas of rats made diabetic by streptozotocin. Results of these dual recording experiments were compared with data from similar experiments performed on non-diabetic retinal microvessels. These experiments revealed that diabetes caused a ~5-fold increase in the rate at which a voltage decays as it axially spreads through the retinal microvasculature. In contrast, the efficacy of radial abluminal cell/endothelial cell transmission was not significantly affected by diabetes. Based on the results of this study, which is the first to characterize how diabetes affects voltage transmission in capillary/arteriolar complexes of any tissue, we concluded that by selectively inhibiting axial transmission, diabetes alters the electrotonic architecture of the retinal microvasculature. This diabetes-induced alteration in the functional organization of the capillary/arteriolar unit is likely to impair its ability to efficiently and effectively regulate blood flow and thereby, may contribute to the progression of sight-threatening complications of diabetic retinopathy.

Although oxidative stress is a hallmark of important vascular disorders such as diabetic retinopathy, it remains unclear why the retinal microvasculature is particularly vulnerable to this pathophysiological condition. We postulated that redox-sensitive ion channels may play a role. Using H(2)O(2) to cause oxidative stress in microvascular complexes freshly isolated from the adult rat retina, we assessed ionic currents, cell viability, intracellular oxidants, and cell calcium by using perforated-patch recordings, trypan blue dye exclusion, and fura-2 fluorescence, respectively. Supporting a role for the oxidant-sensitive ATP-sensitive K (K(ATP)) channels, we found that these channels are activated during exposure of retinal microvessels to H(2)O(2). Furthermore, their inhibition by glibenclamide significantly lessened H(2)O(2)-induced microvascular cell death. Additional experiments established that by increasing the influx of calcium into microvascular cells, the K(ATP) channel-mediated hyperpolarization boosted the vulnerability of these cells to oxidative stress. In addition to the K(ATP) channel-dependent mechanism for increasing the lethality of oxidative stress, we also found that the vulnerability of cells in the capillaries, but not in the arterioles, was further boosted by a K(ATP) channel-independent mechanism, which our experiments indicated involves the oxidant-induced activation of calcium-permeable nonspecific cation channels. Taken together, our findings support a working model in which both K(ATP) channel-independent and K(ATP) channel-dependent mechanisms render the capillaries of the retina particularly vulnerable to oxidative stress. Identification of these previously unappreciated mechanisms for boosting the lethality of oxidants may provide new targets for pharmacologically limiting damage to the retinal microvasculature during periods of oxidative stress.