PDE5A and hypertensive disorder: Of note, RhoBTB1 serves as a CRL3 substrate adaptor for the ubiquitination of PDE5, further suggesting that enhanced binding of variant CUL3 with substrate adaptors results in impaired substrate (i.e., RhoA and PDE5) ubiquitination and diminished vascular compliance in FHHt hypertension (Fig. 2).