Homeobox A4 suppresses vascular remodeling by repressing YAP/TEAD transcriptional activity

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Signaling Pathways

Background:

• The Hippo signaling pathway regulates cardiovascular disease pathophysiology.
• Yes-associated protein (YAP) and transcriptional enhancer activator domain (TEAD) are key Hippo pathway components influencing vascular smooth muscle cell (VSMC) phenotype.
• The intrinsic regulators of YAP/TEAD activity in vascular pathophysiology are not fully understood.

Purpose of the Study:

• To identify intrinsic regulators of YAP/TEAD transcriptional activity in vascular pathophysiology.
• To elucidate the role of Homeobox A4 (HOXA4) in regulating VSMC phenotype and vascular remodeling.

Main Methods:

• Lentiviral shRNA screening to identify regulators of YAP/TEAD activity.
• In vitro studies using human VSMCs to assess HOXA4 function.
• Generation and analysis of Hoxa4-deficient mice, including in vivo studies of vascular remodeling post-carotid artery ligation.

Main Results:

• Homeobox A4 (HOXA4) was identified as a repressor of YAP/TEAD transcriptional activity.
• HOXA4 interacts with TEAD, competing with YAP binding and attenuating YAP/TEAD-mediated transcription.
• HOXA4 maintains VSMC differentiation by inhibiting YAP/TEAD-induced phenotypic switching.
• Hoxa4 deficiency in mice led to decreased smooth muscle-specific gene expression and exacerbated vascular remodeling.

Conclusions:

• HOXA4 acts as a repressor of VSMC phenotypic switching.
• HOXA4 inhibits YAP/TEAD-mediated transcription, thereby maintaining VSMC differentiation.
• HOXA4 plays a critical role in regulating vascular remodeling and smooth muscle cell function.