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.
Highlights
Pulmonary hypertension (PH) is a fatal clinical diseases that can be idiopathic or secondary to heart, pulmonary, and vascular diseases
Validation of Rat PH Model Induced by Hypoxia Body weight, mean pulmonary artery pressure and the Fulton index of rat have been obtained to validate the successful induction of PH
When rats stay in hypoxia environment, the initial contraction of pulmonary arteriole leads to a temporary increase of pulmonary arterial pressure
Summary
Pulmonary hypertension (PH) is a fatal clinical diseases that can be idiopathic or secondary to heart, pulmonary, and vascular diseases. The most important characteristic of pulmonary vascular remodeling is the thickening of the vascular intima, media, and adventitia, which is generally thought to result from cell hypertrophy, proliferation, migration, and extracellular matrix deposition. This process involves many cell types, including endothelial cells, smooth muscle cells, fibroblasts, inflammatory cells, and platelets. One of the major finding is that Notch signaling pathway plays a crucial role in the angiogensis and vascular remodeling [8,9,10,11,12,13,14,15,16,17,18]
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