Transient Receptor Potential Melastatin 7 Promotes Vascular Adventitial Fibroblasts Phenotypic Transformation and Inflammatory Reaction Induced by Mechanical Stretching Stress via p38 MAPK/JNK Pathway

Abstract

Remodeling of the arteries is one of the pathological bases of hypertension. We have previously shown that transient receptor potential melastatin 7 (TRPM7) aggravates the vascular adventitial remodeling caused by pressure overload in the transverse aortic constriction (TAC) model. In this study, we sought to explore the functional expression and downstream signaling of TRPM7 in vascular adventitial fibroblasts (AFs) stimulated by mechanical stretching stress (MSS). The expression of TRPM7 was upregulated with a concomitant translocation to the cytoplasm in the AFs stimulated with 20% MSS. Meanwhile, the expression of α-smooth muscle actin (α-SMA), a marker of transformation from AFs to myofibroblasts (MFs) was also increased. Moreover, AF-conditioned medium caused a significant migration of macrophages after treatment with MSS and contained high levels of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Pharmacological and RNA interference approaches using the TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB) and specific anti-TRPM7 small interfering RNA (si­RNA-TRPM7) abrogated these changes significantly. Further exploration uncloaked that inhibition of TRPM7 reduced the phosphorylation of p38 MAP kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) in the AFs stimulated with MSS. Furthermore, inhibition of the phosphorylation of p38MAPK or JNK could also alleviate the MSS-induced expression of α-SMA and secretion of inflammatory factors. These observations indicate that activated TRPM7 participates in the phenotypic transformation and inflammatory action of AFs in response to MSS through the p38MAPK/JNK pathway and suggest that TRPM7 may be a potential therapeutic target for vascular remodeling caused by hemodynamic changes in hypertension.

Norepinephrine acting on adventitial fibroblasts stimulates vascular smooth muscle cell proliferation via promoting small extracellular vesicle release

“…It is known that phenotypic transformation of vascular AFs to myofibroblasts plays an important role in vascular remodeling 44 . α-SMA is used as a marker of the AFs phenotypic transformation 45 - 47 . The α-SMA protein was upregulated in SHR compared with that in WKY.…”

Aqueous extract of Salvia miltiorrhiza Bunge reduces blood pressure through inhibiting oxidative stress, inflammation and fibrosis of adventitia in primary hypertension

“…In a model of chronic nitric oxide inhibition, which leads to systemic hypertension, the thickness of adventitia and the number of cells increased before change in the media or intima (Schulze-Bauer et al, 2002). Under conditions of elevated blood pressure, the adventitia becomes the dominant component of the vascular wall due to its obvious stiffening (Liu et al, 2021). As a result, adventitial fibroblasts are considered to be the most sensitive cells to detect hypertensive states (McGrath et al, 2005).…”

Potential of the TRPM7 channel as a novel therapeutic target for pulmonary arterial hypertension

“…The involvement of TRPM7 channels in cardiovascular remodeling has been reported ( 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ). TRPM7 channels are activated by oxidative, mechanical, and osmotic stress, thereby contributing to various physiological events, such as inflammation, fibrosis, cell migration, contraction, and cell growth ( 53 ).…”