Role of the Balance of Akt and MAPK Pathways in the Exercise-Regulated Phenotype Switching in Spontaneously Hypertensive Rats.

Lin Zhang,Yimin Zhang,Lijun Shi,Ying Wu,Fanxing Zeng,Yanyan Zhang,Jingjing Yu

doi:10.3390/ijms20225690

Abstract

The mechanisms regulating vascular smooth muscle cell (VSMC) phenotype switching and the critical signal modulation affecting the VSMCs remain controversial. Physical exercise acts as an effective drug in preventing elevated blood pressure and improving vascular function. This study was designed to explore the influence of aerobic exercise on the suppression of VSMC phenotype switching by balancing of the Akt, also known as PKB (protein kinase B) and mitogen-activated protein kinase (MAPK) signaling pathways. Spontaneously hypertensive rats (SHRs) and normotensive rats were subjected to exercise treatment before measuring the vascular morphological and structural performances. Exercise induced reverse expression of VSMC protein markers (α-SM-actin, calponin, and osteopontin (OPN)) in spontaneously hypertensive rats. It is noteworthy that the low expression of phosphorylated Akt significantly decreased the expression of VSMC contractile phenotype markers (α-SM-actin and calponin) and increased the expression of the VSMC synthetic phenotype marker (OPN). However, the MAPK signal pathway exerts an opposite effect. VSMCs and whole vessels were treated by inhibitors, namely the p-Akt inhibitor, p-ERK inhibitor, and p-p38 MAPK inhibitors. VSMC phenotype markers were reversed. It is important to note that a significant reverse regulatory relationship was observed between the expression levels of MAPK and the contractile markers in both normotensive and spontaneously hypertensive rats. We demonstrate that aerobic exercise regulates the VSMC phenotype switching by balancing the Akt and MAPK signaling pathways in SHRs.

Highlights

According to the mounting evidence, the vascular smooth muscle cell (VSMC) phenotype switching from a contractile phenotype state to a synthetic phenotype state plays a crucial role in a variety of cardiovascular diseases, such as atherosclerosis [1], hypertension [2], coronary heart disease [3], and diabetes [4]
Significant differences were observed between sedentary spontaneously hypertensive rats (SHR-SED) and sedentary normotensive rats (Wistar-Kyoto rat-SED, Wistar-Kyoto rats (WKY)-SED), and spontaneously hypertensive rats showed significantly higher SBP, DBP, MAP, and heart rate (HR) (p < 0.01)
Exercise reduced SBP in both SHR-EX (p < 0.01) and WKY-EX (p < 0.05) groups compared with their matched sedentary groups

Summary

Introduction

According to the mounting evidence, the vascular smooth muscle cell (VSMC) phenotype switching from a contractile (differentiated) phenotype state to a synthetic (proliferated, or dedifferentiated) phenotype state plays a crucial role in a variety of cardiovascular diseases, such as atherosclerosis [1], hypertension [2], coronary heart disease [3], and diabetes [4]. Phenotype switching is characterized by changes in morphology, proliferation, and migration rates, and the expression of different marker proteins [9]. A synthetic or proliferative phenotype, which has a stronger proliferation and migration ability, is significantly expressed in blood arteries. A differentiated or contractile phenotype is predominant in the blood vessels of healthy adults. VSMCs undergo a switch from a contractile phenotype to a synthetic or proliferative phenotype after vessel injury. Under stressed or pathological conditions, highly dedifferentiated contractile cells re-enter the cell cycle, become dedifferentiated, and assume a synthetic or proliferative phenotype. Once the injury is resolved, VSMCs return to a non-proliferative, contractile phenotype [10,11,12]

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