title: Tsc1 deficiency-mediated mTOR hyperactivation in vascular endothelial cells causes angiogenesis defects and embryonic lethality.
abstract: This is a study on the role of tuberous sclerosis complex1 (TSC1) mutation and mTOR activation in endothelial cells during angiogenic and embryonic development. Past studies had shown that Tsc1/Tsc2 mutant genes lead to overactivation of mTOR in the regulating pathways in developing fetus. We used conditional Cre-loxp gene knockout approach to delete Tsc1 in mice's endothelial cells in our experimental models. Similarly, activation of mTOR signaling in endothelial cells of these embryos (Tie2-Cre/Tsc1(-/-)) was found. Majority of Tie2-Cre/Tsc1(-/-) embryos died at embryonic day 14.5 in utero. Cardiovascular defects, subcutaneous edema and hemorrhage were present among them. Whole-mount immunostaining in these embryos revealed a disorganized vascular network, defective sprouting of vessels in yolk sac and thickening of the labyrinth layer in the placenta. A thinner ventricular wall with disorganized trabeculae was present in the hearts of Tie2-Cre/Tsc1(-/-) embryos. Endothelial cells in Tsc1-deficient mice showed defective mitochondrial and endoplasmic reticular morphology, but no significant change was observed in cell junctions. The mutant embryos displayed significantly reduced cell proliferation, increased apoptosis and disturbed expression of angiogenic factors. A cohort of mice was treated prenatally with mTOR inhibitor rapamycin. The offspring of these mutant mice survived up to 22 days after birth. It was concluded that physiological TSC1-mTOR signaling in endothelial cells is crucial for vascular development and embryogenesis. We postulated that disruption of normal angiogenic pathways through hyperactive mTOR signaling maybe the mechanism that lead to deranged vascular pathogenesis in the tuberous sclerosis complex.
authors.affiliation: Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Aiping
authors.initials: A
authors.lastname: Ma
authors.forename: Lianmei
authors.initials: L
authors.lastname: Wang
authors.forename: Yunzhou
authors.initials: Y
authors.lastname: Gao
authors.forename: Zai
authors.initials: Z
authors.lastname: Chang
authors.forename: Haiyong
authors.initials: H
authors.lastname: Peng
authors.forename: Ni
authors.initials: N
authors.lastname: Zeng
authors.forename: Yao-Song
authors.initials: YS
authors.lastname: Gui
authors.forename: Xinlun
authors.initials: X
authors.lastname: Tian
authors.forename: Xue
authors.initials: X
authors.lastname: Li
authors.forename: Baiqiang
authors.initials: B
authors.lastname: Cai
authors.forename: Hongbing
authors.initials: H
authors.lastname: Zhang
authors.forename: Kai-Feng
authors.initials: KF
authors.lastname: Xu
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005313:Fetal Death / Q000235:genetics; D006720:Homozygote; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000235:genetics / Q000473:pathology; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D015017:Yolk Sac / Q000098:blood supply / Q000473:pathology
chemical_list: C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus