Increased Subpleural Pulmonary Arteriolar Tone Associated with Inhibition of Nitric Oxide Synthase in a Mouse Model of Type‐1 Diabetes

Abstract

Type‐1 diabetes, characterized by elevation of blood glucose, inflammation and oxidative stress, results in endothelial injury that alters nitric oxide (NO) signaling and impairs microvascular regulation in a variety of vascular beds. NO signaling also plays a prominent role in the modulation of alveolar perfusion. Therefore, the lungs may be particularly vulnerable to diabetes‐induced endothelial changes. We hypothesized that diabetes‐induced oxidative injury, resulting in decreased NO bioavailability and enhanced fibrinogen‐endothelial interaction, induces endothelial injury and pulmonary microvascular dysfunction in the mouse lung. The effects of acute NO synthase (NOS) inhibition with L‐NAME on subpleural arterioles were examined in streptozotocin‐treated C57BL/6J mice (STZ) and their saline‐treated controls (Control). Microvascular changes were assessed by intravital microscopy of the right lung in anesthetized mice (7 to 11 months old) with open chest and ventilated lungs. Pulmonary arteriolar diameters (ranging from 27.2 – 48.7 μm) were measured before and after acute administration of the nitric oxide synthase (NOS) inhibitor, L‐NAME (0.1mg/g body wt). L‐NAME caused a 13.6 ± 7.5% constriction (n=5, p=0.034) in Control mice. In contrast, there was an 18.0 ± 11% dilation (p<0.009, n=5) in STZ mice. Intra‐arterial administration of fluorescently‐labeled fibrinogen in STZ mice, without L‐NAME treatment, resulted in adherence of fibrinogen in the microvascular network, indicating endothelial injury. These data suggest that diabetes‐induced systemic effects may affect lung endothelial function. Control mice displayed a physiological vasoconstriction response to L‐NAME resulting from a loss of the NO vasodilator influence. In contrast, while L‐NAME may have decreased bioavailable NO in the diabetic lung, inhibition of NOS with L‐NAME appeared to have a vasodilator effect by decreasing formation of reactive nitrogen species or by unmasking another vasodilator. We conclude that diabetes may adversely affect lung microvasculature by inducing inflammation and decreasing NO bioavailability. Altered NO‐induced responses may subsequently cause significant pulmonary endothelial injury and microvascular dysfunction that could lead to ventilation‐perfusion abnormalities and exacerbate systemic complications of diabetesSupport or Funding InformationUniversity of Louisville, School of Medicine Collaborative Enhancement GrantThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.