title: Notch signaling change in pulmonary vascular remodeling in rats with pulmonary hypertension and its implication for therapeutic intervention.
abstract: Pulmonary hypertension (PH) is a fatal disease that lacks an effective therapy. Notch signaling pathway plays a crucial role in the angiogenesis and vascular remodeling. However, its roles in vascular remodeling in PH have not been well studied. In the current study, using hypoxia-induced PH model in rat, we examined the expression of Notch and its downstream factors. Then, we used vessel strip culture system and γ-secretase inhibitor DAPT, a Notch signaling inhibitor to determine the effect of Notch signaling in vascular remodeling and its potential therapeutic value. Our results indicated that Notch 1-4 were detected in the lung tissue with variable levels in different cell types such as smooth muscle cells and endothelial cells of pulmonary artery, bronchia, and alveoli. In addition, following the PH induction, all of Notch1, Notch3, Notch4 receptor, and downstream factor, HERP1 in pulmonary arteries, mRNA expressions were increased with a peak at 1-2 weeks. Furthermore, the vessel wall thickness from rats with hypoxia treatment increased after cultured for 8 days, which could be decreased approximately 30% by DAPT, accompanied with significant increase of expression level of apoptotic factors (caspase-3 and Bax) and transformation of vascular smooth muscle cell (VSMC) phenotype from synthetic towards contractile. In conclusion, the current study suggested Notch pathway plays an important role in pulmonary vascular remodeling in PH and targeting Notch signaling pathway could be a valuable approach to design new therapy for PH.
authors.affiliation: Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China. iaqiao@163.com
authors.forename: Lina
authors.initials: L
authors.lastname: Qiao
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.forename: Kun
authors.initials: K
authors.lastname: Shi
authors.forename: Tongfu
authors.initials: T
authors.lastname: Zhou
authors.forename: Yimin
authors.initials: Y
authors.lastname: Hua
authors.forename: Hanmin
authors.initials: H
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000150:complications / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D013194:Staining and Labeling
chemical_list: D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch