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SM22?+ vascular mural cells are essential for vessel stability in tumors and undergo phenotype transition regulated by Notch signaling.

ABSTRACT: BACKGROUND:Malformation of blood vessels represents a hallmark of cancers, but the role and regulation of vascular mural cells (vMCs), including vascular smooth muscle cells (vSMCs) and pericytes, in tumors has not been fully understood. SM22? has been identified as a marker of vSMCs. This study aims at elucidating the function and regulation of SM22?+ mural cells (SM22-MCs) in tumor stroma. METHODS:Gene-modified mice with a SM22?-CreERT2 transgene were employed to deplete SM22-MCs or activate/block Notch signaling in these cells. vSMCs from mouse dorsal aorta (vSMCs-DA) were cultured in vitro. RNA-seq was used to compare gene expression profiles. qRT-PCR and western blotting were used to determine gene expression level. Immunofluorescence was used to observe morphological alterations in tumors. RESULTS:SM22-MCs are essential for stabilizing tumor vasculature. Notch signaling was downregulated in tumor-derived SM22-MCs and vSMCs-DA treated with cancer cell-derived conditioned medium. Notch activation in SM22-MCs normalized tumor vasculature and repressed tumor growth. On the other hand, Notch disruption aggravated abnormal tumor vasculature and promoted growth and metastasis. Gene expression profiling of vSMCs-DA showed that Notch activation enhances their contractile phenotype and suppresses their secretory phenotype, further attenuating the invasion and proliferation of tumor cells. In contrast, Notch blockade in vSMCs-DA mitigated their contractile phenotype while strengthened the secretory phenotype. CONCLUSION:SM22-MCs facilitate vessel stability in tumors, and they gain a secretory phenotype and promote tumor malignancy in the absence of Notch signaling.

SUBMITTER: Zhang X

PROVIDER: S-EPMC7331127 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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SM22α<sup>+</sup> vascular mural cells are essential for vessel stability in tumors and undergo phenotype transition regulated by Notch signaling.

Zhang Xinxin X Yan Xianchun X Cao Jing J Yang Ziyan Z Cao Xiuli X Zhang Yufei Y Liang Liang L Zheng Minhua M Liu Xiaowei X Zhang Jian J Han Hua H

Journal of experimental & clinical cancer research : CR 20200702 1

<h4>Background</h4>Malformation of blood vessels represents a hallmark of cancers, but the role and regulation of vascular mural cells (vMCs), including vascular smooth muscle cells (vSMCs) and pericytes, in tumors has not been fully understood. SM22α has been identified as a marker of vSMCs. This study aims at elucidating the function and regulation of SM22α<sup>+</sup> mural cells (SM22-MCs) in tumor stroma.<h4>Methods</h4>Gene-modified mice with a SM22α-CreER<sup>T2</sup> transgene were emplo ...[more]

PMID: 32616053

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Project description:BackgroundPericytes and vascular smooth muscle cells, collectively known as mural cells, are recruited through PDGFB (platelet-derived growth factor B)-PDGFRB (platelet-derived growth factor receptor beta) signaling. MCs are essential for vascular integrity, and their loss has been associated with numerous diseases. Most of this knowledge is based on studies in which MCs are insufficiently recruited or fully absent upon inducible ablation. In contrast, little is known about the physiological consequences that result from impairment of specific MC functions. Here, we characterize the role of the transcription factor SRF (serum response factor) in MCs and study its function in developmental and pathological contexts.MethodsWe generated a mouse model of MC-specific inducible Srf gene deletion and studied its consequences during retinal angiogenesis using RNA-sequencing, immunohistology, in vivo live imaging, and in vitro techniques.ResultsBy postnatal day 6, pericytes lacking SRF were morphologically abnormal and failed to properly comigrate with angiogenic sprouts. As a consequence, pericyte-deficient vessels at the retinal sprouting front became dilated and leaky. By postnatal day 12, also the vascular smooth muscle cells had lost SRF, which coincided with the formation of pathological arteriovenous shunts. Mechanistically, we show that PDGFB-dependent SRF activation is mediated via MRTF (myocardin-related transcription factor) cofactors. We further show that MRTF-SRF signaling promotes pathological pericyte activation during ischemic retinopathy. RNA-sequencing, immunohistology, in vivo live imaging, and in vitro experiments demonstrated that SRF regulates expression of contractile SMC proteins essential to maintain the vascular tone.ConclusionsSRF is crucial for distinct functions in pericytes and vascular smooth muscle cells. SRF directs pericyte migration downstream of PDGFRB signaling and mediates pathological pericyte activation during ischemic retinopathy. In vascular smooth muscle cells, SRF is essential for expression of the contractile machinery, and its deletion triggers formation of arteriovenous shunts. These essential roles in physiological and pathological contexts provide a rationale for novel therapeutic approaches through targeting SRF activity in MCs.

Dataset Information

SM22?+ vascular mural cells are essential for vessel stability in tumors and undergo phenotype transition regulated by Notch signaling.

Publications

SM22α<sup>+</sup> vascular mural cells are essential for vessel stability in tumors and undergo phenotype transition regulated by Notch signaling.

Similar Datasets

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