Deletion of DGCR8 in VSMCs of adult mice results in loss of vascular reactivity, reduced blood pressure and neointima formation
2019-03-02T15:52:03Z (GMT) by
DiGeorge syndrome chromosomal region 8 (DGCR8), a double-stranded-RNA-binding protein,<br>participates in the miRNA biogenesis pathway and contributes to miRNA maturation by interacting<br>with the RNAase III enzyme Drosha in cell nuclei. To investigate the role of DGCR8 in vascular smooth<br>muscle cells (VSMCs) at the postnatal stages, we generated tamoxifen-inducible VSMC specific<br>knockout (iKO) mice by crossing DGCR8loxp/loxp with VSMC specific tamoxifen-inducible Cre transgenic<br>mice SMA-Cre-ERT2. DGCR8iKO mice display reduced body weight one month following tamoxifen<br>treatment and died around 3 months. Blood pressure and vascular reactivity were significantly<br>reduced in DGCR8iKO mice compared to control. Furthermore, loss of DGCR8 in VSMCs inhibited cell<br>proliferation, migration and neointima formation. VSMC differentiation marker genes, including SMA<br>and SM22, were downregulated in DGCR8 iKO mice. The majority of miRNAs were downregulated in<br>DGCR8iKO mice. Disruption of the DGCR8-mediated miRNA biogenesis pathway attenuated multiple<br>signaling pathways including ERK1/2 and AKT. Our results demonstrate that the DGCR8-mediated<br>miRNA pathway is required for maintaining blood pressure, vascular reactivity and vascular wall<br>remodeling at the postnatal stages.