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.