Increased pulmonary arteriolar tone associated with lung oxidative stress and nitric oxide in a mouse model of Alzheimer's disease. Issue 17 (7th September 2016)

• Record Type: Journal Article
• Authors: Roberts, Andrew M.; Jagadapillai, Rekha; Vaishnav, Radhika A.; Friedland, Robert P.; Drinovac, Robert; Lin, Xingyu; Gozal, Evelyne
• Is Part Of: Physiological reports. Volume 4:Issue 17(2016)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2016-09-07
• Subjects: Amyloid precursor protein -- endothelial dysfunction -- lung microcirculation -- neuroinflammation -- reactive nitrogen species; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.12953
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: Vascular dysfunction and decreased cerebral blood flow are linked to Alzheimer's disease (AD). Loss of endothelial nitric oxide (NO) and oxidative stress in human cerebrovascular endothelium increase expression of amyloid precursor protein (APP) and enhance production of the A β peptide, suggesting that loss of endothelial NO contributes to AD pathology. We hypothesize that decreased systemic NO bioavailability in AD may also impact lung microcirculation and induce pulmonary endothelial dysfunction. The acute effect of NO synthase (NOS) inhibition on pulmonary arteriolar tone was assessed in a transgenic mouse model (TgAD) of AD (C57BL/6‐Tg(Thy1‐APPSwDutIowa)BWevn/Mmjax) and age‐matched wild‐type controls (C57BL/6J). Arteriolar diameters were measured before and after the administration of the NOS inhibitor, L‐NAME. Lung superoxide formation (DHE) and formation of nitrotyrosine (3‐NT) were assessed as indicators of oxidative stress, inducible NOS (iNOS) and tumor necrosis factor alpha (TNF‐ α ) expression as indicators of inflammation. Administration of L‐NAME caused either significant pulmonary arteriolar constriction or no change from baseline tone in wild‐type (WT) mice, and significant arteriolar dilation in TgAD mice. DHE, 3‐NT, TNF‐ α, and iNOS expression were higher in TgAD lung tissue, compared to WT mice. These data suggest L‐NAME could induce increased pulmonary arteriolar tone in WT mice from loss of bioavailable NO. In contrast, NOS inhibition with L‐NAME had a vasodilator effect in TgAD mice, potentially caused by decreased reactive nitrogen species formation, while significant oxidative stress and inflammation were present. We conclude that AD may increase pulmonary microvascular tone as a result of loss of bioavailable NO and increased oxidative stress. Our findings suggest that AD may have systemic microvascular implications beyond central neural control mechanisms. Abstract : Vascular dysfunction and decreased cerebral blood flow are linked to Alzheimer's disease (AD) and involve amyloid beta inducing loss of endothelial nitric oxide (NO). To determine if decreased systemic NO bioavailability in AD may also impact lung microcirculation, acute effects of NO synthase inhibition were compared in transgenic AD and wild‐type control mice. Our data suggest that AD may alter pulmonary arteriolar function as a result of loss of bioavailable NO and increased oxidative stress, suggesting that AD may have systemic microvascular implications.