RGS5 maintaining vascular homeostasis is altered by the tumor microenvironment
Peng Kong1, Xu Wang1,2, Ya-Kun Gao1
1Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China.
Background:
Regulator of G protein signaling 5 (RGS5), as a negative regulator of G protein-coupled receptor (GPCR) signaling, is highly expressed in arterial VSMCs and pericytes, which is involved in VSMC phenotypic heterogeneity and vascular remodeling in tumors. However, its role in normal and tumor vascular remodeling is controversial.
Methods:
RGS5 knockout (Rgs5-KO) mice and RGS5 overexpression or knockdown in VSMCs in vivo by adeno-associated virus type 9 (AAV) carrying RGS5 cDNA or small hairpin RNA (shRNA) targeting RGS5 were used to determine the functional significance of RGS5 in vascular inflammation. RGS5 expression in the triple-negative (TNBCs) and non-triple-negative breast cancers (Non-TNBCs) was determined by immunofluorescent and immunohistochemical staining. The effect of breast cancer cell-conditioned media (BC-CM) on the pro-inflammatory phenotype of VSMCs was measured by phagocytic activity assays, adhesion assay and Western blot.
Results:
We identified that knockout and VSMC-specific knockdown of RGS5 exacerbated accumulation and pyroptosis of pro-inflammatory VSMCs, resulting in vascular remodeling, which was negated by VSMC-specific RGS5 overexpression. In contrast, in the context of breast cancer tissues, the role of RGS5 was completely disrupted. RGS5 expression was increased in the triple-negative breast cancer (TNBC) tissues and in the tumor blood vessels, accompanied with an extensive vascular network. VSMCs treated with BC-CM displayed enhanced pro-inflammatory phenotype and higher adherent with macrophages. Furthermore, tumor-derived RGS5 could be transferred into VSMCs.
Conclusions:
These findings suggest that tumor microenvironment shifts the function of RGS5 from anti-inflammation to pro-inflammation and induces the pro-inflammatory phenotype of VSMCs that is favorable for tumor metastasis.
Insights
Regulator of G protein signaling 5 (RGS5) normally prevents vascular inflammation but promotes it in breast tumors. Tumor environments alter RGS5 function, aiding cancer progression and metastasis.
Area of Science:
- Vascular Biology
- Oncology
- Cell Signaling
Background:
- Regulator of G protein signaling 5 (RGS5) is highly expressed in vascular smooth muscle cells (VSMCs) and pericytes.
- RGS5 negatively regulates G protein-coupled receptor (GPCR) signaling and influences VSMC phenotype and tumor vascular remodeling.
- Its precise role in normal versus tumor vascular remodeling remains controversial.
Purpose of the Study:
- To investigate the functional significance of RGS5 in vascular inflammation and remodeling.
- To determine RGS5 expression in breast cancer tissues and its role in tumor vascularization.
- To elucidate how breast cancer cell-conditioned media affects VSMC phenotype.
Main Methods:
- Utilized RGS5 knockout mice and adeno-associated virus (AAV)-mediated in vivo RGS5 manipulation in VSMCs.
- Assessed RGS5 expression in triple-negative breast cancer (TNBC) and non-TNBC tissues via immunofluorescence and immunohistochemistry.
- Evaluated VSMC pro-inflammatory phenotype using phagocytic activity assays, adhesion assays, and Western blot analysis after exposure to breast cancer cell-conditioned media (BC-CM).
Main Results:
- RGS5 deficiency exacerbated VSMC accumulation and pyroptosis, leading to vascular remodeling, which was reversed by RGS5 overexpression.
- In breast cancer, RGS5 expression was elevated in TNBC tissues and tumor vasculature, correlating with increased vascular networks.
- BC-CM induced a pro-inflammatory and adhesive VSMC phenotype, with evidence of tumor-derived RGS5 transfer to VSMCs.
Conclusions:
- The tumor microenvironment reprograms RGS5 from an anti-inflammatory to a pro-inflammatory mediator.
- Tumor-induced RGS5 promotes a pro-inflammatory VSMC phenotype that supports tumor metastasis.
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