Increased pulmonary arteriolar tone associated with lung oxidative stress and nitric oxide in a mouse model of Alzheimer's disease.

Andrew M Roberts,Xingyu Lin,Robert Drinovac,Rekha Jagadapillai,Evelyne Gozal,Radhika A Vaishnav,Robert P Friedland

doi:10.14814/phy2.12953

Andrew M Roberts, Xingyu Lin + Show 5 more

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https://doi.org/10.14814/phy2.12953

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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 Aβ 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.

Highlights

Alzheimer’s disease (AD) characteristically involves progression of amyloid-b (Ab) pathology in the brain and is a multifactorial process associated with oxidative stress, inflammation, and neurovascular damage
We investigated whether the AD pathogenic process causes pulmonary microvascular dysfunction associated with altered nitric oxide (NO) expression and oxidative injury in the lungs of AD transgenic mice, compared to their agematched wild-type controls
Based on the well-described cerebral microvascular injury and dysfunction initiated by inflammatory effects of Ab and altered NO synthesis, identification of a similar injury in the pulmonary microcirculation would indicate that AD may have systemic microvascular effects in vulnerable tissues

Summary

Introduction

Alzheimer’s disease (AD) characteristically involves progression of amyloid-b (Ab) pathology in the brain and is a multifactorial process associated with oxidative stress, inflammation, and neurovascular damage. Ab, derived from amyloid precursor protein (APP), causes neuroinflammation that leads to microvascular injury, dysfunction, and neurodegeneration (Sutton et al 1999; Dudal et al 2004; Paul et al 2007). Cerebral amyloid angiopathy is a hallmark of AD (Thomas et al 1996; Sutton et al 1997) and increased Ab is recognized as a cause of a 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society

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