Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility

A novel role for PGE2-EP4 in the developmental programming of the mouse ductus arteriosus: consequences for vessel maturation and function

“…Recent studies have identified genes associated with remodeling of the mouse DA after birth that could be important for understanding remodeling deficits in the EP 4 KO ( 112 ) but transcriptional analysis of postbirth KO DAs are not available for comparison. Interestingly, recent studies into the Prdm6-KO mouse model revealed both decreased EP 4 expression and an inability to constrict in response to oxygen ( 113 ). At first, these results appear to contradict our findings, but previous studies of D15 DAs found a partially intact oxygen response, indicating that the DA’s oxygen-sensing mechanism begins development before EP 4 begins its developmental role.…”

Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants

“…PRDM6 is one of the few known causes of familial non‐syndromic PDA (Li et al, 2016). PRDM6 encodes a transcription factor (also called PRISM) expressed in the cardiac outflow tract and DA that promotes SMC differentiation (Davis et al, 2006; Hong et al, 2022; Zou et al, 2023). Functional evidence from in vitro cell lines together with in vivo mouse model data suggest a loss‐of‐function mechanism; gene depletion leads to dysregulation of genes critical for SMC differentiation with resultant disruption of vascular remodeling, decreased DA tone and contractility, and persistent ductal patency (Hong et al, 2022; Li et al, 2016; Zou et al, 2023).…”

“…PRDM6 encodes PR domain‐containing protein 6, a smooth‐muscle‐cell‐specific putative histone methyltransferase and transcriptional repressor. Studies of the mouse homolog suggest that PRDM6 directs cardiac neural crest cell (CNCC) differentiation and migration and is critical to ductus arteriosus (DA) closure in mammals after birth (Hong et al, 2022; Zou et al, 2023). We present two unrelated families with PDA and CoA found to harbor PRDM6 variants, representing an expansion of PRDM6‐related disease to include CoA.…”

Epigenetic Alteration of Smooth Muscle Cells Regulates Endothelin-Dependent Blood Pressure and Hypertensive Arterial Remodeling

“…Although the upstream signaling pathways have been explored, many of the underlying molecular and epigenetic mechanisms that regulate SMC phenotypes in cardiovascular pathologies, particularly HTN, remain unknown. Epigenetic mechanisms have been previously shown by our group and others to regulate cell phenotypes and control downstream gene expression in homeostatic and pathologic states [19][20][21]. In particular, epigenetic alteration of chromatin structure by epigenetic enzymes and key transcription factors has been shown to influence SMC phenotype during development and cardiovascular pathology [22][23][24][25][26][27][28].…”