Effect of depletion of GPRC5C from smooth muscle cells (SMC) on gene expression in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE241324 | GEO | 2024/04/05
REPOSITORIES: GEO
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Project description:All current smooth muscle cell (SMC) restricted Cre mice recombine floxed alleles in vascular and visceral SMCs. We generated a tamoxifen-inducible CreERT2 mouse, Itga8-CreERT2, and compared its activity to the widely used Myh11-CreERT2 mouse. Both CreERT2 mice showed similar activity in vascular SMCs; however, Itga8-CreERT2 displayed low activity in visceral SMC-containing tissues (e.g., intestine). Myh11-CreERT2 (but not Itga8-CreERT2) mice exhibited high levels of CreERT2 protein, tamoxifen-independent activity, and an altered transcriptome. Whereas Myh11-CreERT2-mediated knockout of Srf resulted in a lethal intestinal phenotype, loss of Srf with Itga8-CreERT2 (SrfItga8) revealed viable mice with attenuated vascular SMC contractile gene expression, but no evidence of intestinal pathology. Male and female SrfItga8 mice presented with vascular contractile incompetence; however, only male SrfItga8 mice showed systemic changes in blood pressure. These results establish the Itga8-CreERT2 mouse as an alternative to existing SMC Cre strains where gene loss may result in visceral myopathies that obfuscate accurate phenotyping in vascular SMCs.
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Project description:The development of atherosclerosis, a chronic disease characterized by the buildup of plaque in arterial walls, involves the contribution of vascular smooth muscle cells (SMCs) and SMC-derived cells. To better understand the specific role of SMCs in atherosclerosis, a transgenic mouse line expressing EGFP-tagged ribosomal protein L10a (EGFP-L10a) under the SMC-specific αSMA promoter (SMCTRAP mice) was developed, enabling translating ribosome affinity purification followed by sequencing (TRAP-Seq). SMCTRAP mice were crossed with an atherosclerosis model (SMCTRAP-Athero mice). Using TRAP-Seq and bulk RNA-Seq, the aortas of 15-month-old SMCTRAP and SMCTRAP-Athero mice were analyzed to identify atherosclerosis-induced changes in the profiles of SMC ribosome-associated RNA. The results showed high enrichment of known SMC-specific genes in the TRAP fraction, indicating the specificity of the construct. The intersection of SMC-specific genes identified by TRAP-Seq, and atherosclerosis-induced genes identified by bulk RNA-Seq revealed the contribution of SMCs to the expression of several known disease-induced genes, as well as the identification of previously unlinked genes in atherosclerosis that warrant further investigation. These findings provide new insights into the role of SMCs in atherosclerosis and may offer potential targets for future treatments of this chronic disease.
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Project description:Effect of depletion of GPRC5C from smooth muscle cells (SMC) on gene expression in mice
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Project description:Previous efforts to conditionally delete the Srf transcription factor in smooth muscle lineages were met with early demise of the mouse due to a gastrointestinal (GI) obstruction phenotype. We have developed a new, more VSMC selective Cre recombinase mouse (Itga8-CreERT2), that circumvents the GI phenotype thus affording the opportunity to evaluate, in an unambiguous manner, VSMC phenotypes where Srf is reduced. The mice live for at least 6 months post-tamoxifen and here we report the first RNA-seq experiments in mouse aortic SMC where Srf is reduced.
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Project description:Differential gene expression in paired SMC vs. Non-SMC
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Project description:We used a smooth muscle cell-specific mineralocorticoid receptor knockout mouse to generate young and aged MR-intact and SMC-MR-KO aortic miRNA to examine the effect of age on vascular miRNA alterations in the presence and absence of SMC-MR. For more information about the mouse model see: McCurley, A et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med. 2012 Sep;18(9):1429-33 Total miRNA was extracted from young (3-4 mo) and aged male (12mo) MR-intact and SMC-MR-KO mice to investigate aging-induced alterations in vascular miRNA expression
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Project description:Hypoxia provokes adaptive responses of cells, which ensure their energy supply including the adjustment of the transcriptome to match their metabolism. In this context, we explored the transcriptional impact of nuclear factor of activated T-cells 5 (NFAT5) on the function of vascular smooth muscle cells (VSMC) in the hypoxic lung. Exposure to hypoxia induced a rapid nuclear translocation of NFAT5 in cultured murine VSMCs. SMC-specific ablation of Nfat5 (Nfat5(SMC-/-)) increases the systolic pressure in the right ventricle (RVSP) of the mouse heart and impairs its function upon exposure to hypoxia for 7 and 21 days. Analyses of the transcriptome of the lung revealed a robust increase in the expression genes attributed to mitochondrial respiration. Further analyses of hypoxia-exposed pulmonary artery VSMCs revealed that loss of Nfat5 stimulates the expression of multiple mitochondria-related genes encoding cytochrome oxidases while decreasing the expression of lactate dehydrogenase A (Ldha) and phosphofructokinase 3 (Pfkfb3). Both, inhibition of LDHA or PFKFB3 activity and loss of Nfat5 stimulated the mitochondrial production of reactive oxygen species (ROS) in hypoxic pulmonary artery VSMCs while scavenging of ROS normalized the RVSP values in hypoxia-exposed Nfat5(SMC-/-) mice. In summary, our findings suggest a crucial role for NFAT5 in adjusting the transcriptome of hypoxia-exposed pulmonary artery VSMCs to support an adequate glycolysis-centered metabolism. Loss of Nfat5 impairs this response thereby fueling the mitochondrial respiration and ROS production that amplifies the hypoxia-mediated constriction of pulmonary arteries.
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Project description:Poor prognosis of small cell lung cancer (SCLC) is mainly attributed to its highly metastatic capability. Here we identify the SMC and Non-SMC from Rb1L/L/Trp53 L/L mouse model through FACS with NE and mensenchymal markers. In order to identify functions of these two subpopulations during SCLC malignant progression, we compared their metastatic capability by allograft experiment. In addition, we find that the SMC is progressively transited from the Non-SCLC during mouse SCLC malignant progression. Further investigation reveals that genetic disruption of the SWI/SNF chromatin-remodeling complex, in RP model abrogates SMC phenotype maintenance and SCLC metastasis. In search of important downstream regulators, we find that TAZ, the core transcription cofactor of the Hippo pathway, is epigenetically silenced by SWI/SNF complex during this process. Collectively, our data link phenotypic transition to cancer metastasis and identify TAZ as a critical molecular switch that controls SCLC plasticity.
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