PDZK1 Regulates the Stability and Function of ADRB2 to Prevent Vascular Remodelling in Hypertension

In this study, we found that PDZK1, a scaffold protein, interacts with the β₂-adrenergic receptor (ADRB2) through its PDZ domains, stabilising ADRB2 by inhibiting its ubiquitination and proteasomal degradation. This study explored the PDZK1-ADRB2 interaction and its role in hypertension-induced vascular remodelling. Using PDZK1 knockout mice infused with angiotensin II, we found that PDZK1 deficiency further exacerbates angiotensin II-induced hypertension, vascular dysfunction, and vascular remodelling. Mechanistically, PDZK1 stabilises ADRB2 protein by preventing its ubiquitination and proteasomal degradation, thereby maintaining ADRB2-mediated vasodilation. Additionally, PDZK1 prevents ADRB2 internalisation and its interaction with β-arrestin, thereby inhibiting β-arrestin-mediated ERK activation and suppressing vascular smooth muscle cell (VSMC) phenotypic switching. This mechanism contributes to vascular protection under hypertensive conditions. Targeting the PDZK1/ADRB2 interaction may provide a novel therapeutic strategy for hypertension-related vascular complications.