Exploration of the Notch3‐HES5 signal pathway in monocrotaline‐induced pulmonary hypertension using rat model

Abstract

Objective This study explores the role of the Notch3‐HES5 signal pathway in monocrotaline‐induced pulmonary hypertension (PH) using rat models. Method Sprague Dawley rats (n = 45) were randomly grouped into normal group, control group, and model group. Rats in the model group were used to establish the PH rat model. Four weeks after model establishment, right catheterization was used to measure the mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) to analyze hemodynamic changes. The severity of PH was assessed by the right ventricular hypertrophy index (RVHI) and percentage of media thickness (MT%). The expressions of Notch3 and HES5 were determined by ELISA and reverse transcription‐polymerase chain reaction. The correlation of mRNA expressions of Notch3 and HES5 with mPAP was analyzed. Results Rats in the model group had higher mPAP, RVSP, RVHI, and MT% as well as thicker pulmonary arterioles wall than those in the normal group. Immunohistochemistry showed Notch3 and HES5 were mainly expressed in the smooth muscle cell in pulmonary arterioles. In comparison with the normal group, rats in the model group had elevated expressions of Notch3 and HES5. The mean pulmonary arterial pressure was positively related with mRNA expressions of Notch3 and HES5. Conclusion Taken together, our study demonstrates that monocrotaline‐induced PH rats had high expressions of the Notch3‐HES5 signal pathway in the pulmonary arterioles. The signal of the Notch3‐HES5 signal pathway was positively related to the hemodynamics of the lung vasculature.

Notch3 signalling and vascular remodelling in pulmonary arterial hypertension

“…Hes5 siRNA treatment also increased expression of genes for myosin heavy chain 11 and smoothelin, suggesting that inactivation of Hes5-mediated signalling in PAH cells promotes phenotypic switching from a synthetic to a more contractile phenotype [11]. Notch3-Hes5 mRNA expression is also increased in MCT-induced PH in rats, and found to positively correlate with mean pulmonary arterial pressure [82].…”

Notch signalling in healthy and diseased vasculature

“…In an important study, Thistlethwaite and colleagues demonstrated that NOTCH3 was upregulated in patients with PAH and that Notch3 −/− mice were resistant to developing pulmonary hypertension when exposed to low oxygen levels [107]. The involvement of NOTCH3 in PAH has been substantiated by subsequent studies revealing an upregulation of Notch3 in various PAH animal models [108][109][110][111]. Furthermore, the NOTCH3-PAH link has recently been corroborated by the identification of NOTCH3 missense mutations (NOTCH3 G840E and NOTCH3 T900P ) in patients with childhood PAH [112] and a NOTCH3 single nucleotide polymorphism (SNP) segregating with childhood PAH [113].…”