Disruption of the Arnt gene in endothelial cells causes hepatic vascular defects and partial embryonic lethality in mice.
Vascular endothelial cells (ECs) play a critical role in angiogenesis and organogenesis, especially in embryonic liver development. Hypoxia-inducible transcription factors (Hifs) are a key trigger of hypoxic signals, a primary stimulus of angiogenesis. The aryl hydrocarbon receptor nuclear translocator (Arnt), also called Hif-1beta, serves as an obligate heterodimerization partner of Hif-1alpha and Hif-2alpha. Using Cre-Lox technology, the mouse Arnt gene was specifically disrupted in endothelial cells. The resulting mice, designated ArntDeltaEC, developed impaired hepatic vasculature, liver necrosis, and degenerative lesions in cardiac myocytes at the late embryonic stage (E16.5-E18.5), leading to approximately 90% neonatal lethality. Low serum glucose, downregulation of glucose transporter-1 and glucose-6-phosphatase mRNA, and hepatocyte proliferation were observed in ArntDeltaEC embryos. Magnetic resonance imaging on E16.5 embryonic livers revealed that ArntDeltaEC mice had a significant volume of avascular region. ArntDeltaEC mice that survived to the adult stage were fertile, showed normal behavioral activity, but had smaller livers with mild portal fibrosis, dilated blood vessels, abnormal collagen accumulation, and remarkable iron deposition. ArntDeltaEC mice had reduced adiposity, impaired serum lipid homeostasis, and a higher respiratory exchange ratio, indicating they utilized relatively more carbohydrates than their ArntF/F counterparts. In conclusion, endothelial Arnt plays a pivotal role in embryonic liver development. Adult ArntDeltaEC mice carrying embryonic hepatic defects developed what was possibly an early stage of cirrhosis with consequences of limited oxygen availability and altered lipid metabolism.
Yim
Sun Hee
SH
Laboratory of Metabolism, National Cancer Institute, Bethesda, MD 20892, USA.
Shah
Yatrik
Y
Tomita
Shuhei
S
Morris
H Douglas
HD
Gavrilova
Oksana
O
Lambert
Gilles
G
Ward
Jerrold M
JM
Gonzalez
Frank J
FJ
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics*; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000196:embryology / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D008099:Liver / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D012313:RNA / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C497397:Arnt protein, mouse; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D012313:RNA