TY - JOUR
T1 - The role of tumor necrosis factor in triggering activation of natural killer cell, multi-organ mitochondrial dysfunction and hypertension during pregnancy
AU - Jayaram, Aswathi
AU - Deer, Evangeline
AU - Amaral, Lorena M.
AU - Campbell, Nathan
AU - Vaka, Venkata Ramana
AU - Cunningham, Mark
AU - Ibrahim, Tarek
AU - Cornelius, Denise C.
AU - LaMarca, Babbette B.
N1 - Funding Information:
This study was supported by NIH grant RO1HD067541 (BL), NIH grants R00HL130456 and P20GM104357 (DCC), NIH P20GM121334 (BL, LMA), American heart association (AHA) early career award 19CDA34670055 (LMA)
Publisher Copyright:
© 2021 International Society for the Study of Hypertension in Pregnancy
PY - 2021/6
Y1 - 2021/6
N2 - Pre-eclampsia (PE) is a hypertensive disorder of pregnancy associated with chronic inflammation, mitochondrial (mt) dysfunction and fetal demise. Natural Killer cells (NK cells) are critical for the innate immune response against tumors or infection by disrupting cellular mt function and causing cell death. Although NK cells can be stimulated by Tumor necrosis factor alpha (TNF-α), we don't know the role of TNF-α on NK cell mediated mt dysfunction during PE. Our objective was to determine if mechanisms of TNF-α induced hypertension included activation of NK cells and multi-organ mt dysfunction during pregnancy. Pregnant rats were divided into 2 groups: normal pregnant (NP) (n = 18) and NP + TNF-α (n = 18). On gestational day 14, TNF-α (50 ng/ml) was infused via mini-osmotic pump and on day 18, carotid artery catheters were inserted. Blood pressure (MAP) and samples were collected on day 19. TNF-α increased MAP (109 ± 2 vs 100 ± 2, p < 0.05), circulating cytolytic NK cells (0.771 ± 0.328 vs.0.008 ± 0.003% gated, <0.05) and fetal reabsorptions compared to NP rats. Moreover, TNF-α caused mtROS in the placenta (12976 ± 7038 vs 176.9 ± 68.04% fold, p < 0.05) and in the kidney (2191 ± 1027 vs 816 ± 454.7% fold, p < 0.05) compared to NP rats. TNF-α induced hypertension is associated fetal demise, activation of NK cells and multi-organ mt dysfunction which could be mechanisms for fetal demise and hypertension. Understanding of the mechanisms by which TNF-α causes pathology is important for the use of anti-TNF-α therapeutic agents in pregnancies complicated by PE.
AB - Pre-eclampsia (PE) is a hypertensive disorder of pregnancy associated with chronic inflammation, mitochondrial (mt) dysfunction and fetal demise. Natural Killer cells (NK cells) are critical for the innate immune response against tumors or infection by disrupting cellular mt function and causing cell death. Although NK cells can be stimulated by Tumor necrosis factor alpha (TNF-α), we don't know the role of TNF-α on NK cell mediated mt dysfunction during PE. Our objective was to determine if mechanisms of TNF-α induced hypertension included activation of NK cells and multi-organ mt dysfunction during pregnancy. Pregnant rats were divided into 2 groups: normal pregnant (NP) (n = 18) and NP + TNF-α (n = 18). On gestational day 14, TNF-α (50 ng/ml) was infused via mini-osmotic pump and on day 18, carotid artery catheters were inserted. Blood pressure (MAP) and samples were collected on day 19. TNF-α increased MAP (109 ± 2 vs 100 ± 2, p < 0.05), circulating cytolytic NK cells (0.771 ± 0.328 vs.0.008 ± 0.003% gated, <0.05) and fetal reabsorptions compared to NP rats. Moreover, TNF-α caused mtROS in the placenta (12976 ± 7038 vs 176.9 ± 68.04% fold, p < 0.05) and in the kidney (2191 ± 1027 vs 816 ± 454.7% fold, p < 0.05) compared to NP rats. TNF-α induced hypertension is associated fetal demise, activation of NK cells and multi-organ mt dysfunction which could be mechanisms for fetal demise and hypertension. Understanding of the mechanisms by which TNF-α causes pathology is important for the use of anti-TNF-α therapeutic agents in pregnancies complicated by PE.
KW - Cytokines
KW - Fetal demise
KW - Hypertension
KW - Inflammation
KW - Oxidative stress
KW - Pregnancy
UR - http://www.scopus.com/inward/record.url?scp=85102051143&partnerID=8YFLogxK
U2 - 10.1016/j.preghy.2021.02.006
DO - 10.1016/j.preghy.2021.02.006
M3 - Article
C2 - 33677421
AN - SCOPUS:85102051143
SN - 2210-7789
VL - 24
SP - 65
EP - 72
JO - Pregnancy Hypertension
JF - Pregnancy Hypertension
ER -