Increased pulmonary arteriolar tone associated with lung oxidative stress and nitric oxide in a mouse model of Alzheimer's disease.
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.
Department of Physiology, School of Medicine University of Louisville, Louisville, Kentucky, 40202 Department of Pediatrics, School of Medicine University of Louisville, Louisville, Kentucky, 40202 andrew.roberts@louisville.edu.
Andrew M
AM
Roberts
Department of Pediatrics, School of Medicine University of Louisville, Louisville, Kentucky, 40202.
Rekha
R
Jagadapillai
Department of Physiology, School of Medicine University of Louisville, Louisville, Kentucky, 40202 Department of Neurology, School of Medicine University of Louisville, Louisville, Kentucky, 40202.
Radhika A
RA
Vaishnav
Department of Neurology, School of Medicine University of Louisville, Louisville, Kentucky, 40202 Department of Anatomical Sciences and Neurobiology, School of Medicine University of Louisville, Louisville, Kentucky, 40202.
Robert P
RP
Friedland
Department of Physiology, School of Medicine University of Louisville, Louisville, Kentucky, 40202.
Robert
R
Drinovac
Department of Pediatrics, School of Medicine University of Louisville, Louisville, Kentucky, 40202 Department of Thoracic Surgery, the First Hospital of Jilin University, Changchun, China.
Xingyu
X
Lin
Department of Physiology, School of Medicine University of Louisville, Louisville, Kentucky, 40202 Department of Pediatrics, School of Medicine University of Louisville, Louisville, Kentucky, 40202.
Evelyne
E
Gozal
D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002560:Cerebrovascular Circulation / Q000502:physiology; D004195:Disease Models, Animal; D004727:Endothelium / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation / Q000187:drug effects*; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D013481:Superoxides / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D013481:Superoxides; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
Amyloid precursor protein; endothelial dysfunction; lung microcirculation; neuroinflammation; reactive nitrogen species