The 2023 Walter B. Cannon Award Lecture: Mechanisms Regulating Vascular Function and Blood Pressure by the PPARγ-RhoBTB1-CUL3 Pathway

Human genetic clinical trial data suggest that PPARγ, a nuclear receptor transcription factor plays an important role in the regulation of arterial blood pressure. The examination of a series of novel animal models, coupled with transcriptomic and proteomic analysis has reveal that PPARγ and its target genes employ diverse pathways to regulate vascular function and blood pressure. In endothelium, PPARγ target genes promote an antioxidant state, stimulating both nitric oxide (NO) synthesis and bioavailability, essential components of endothelial—smooth muscle communication. In vascular smooth muscle, PPARγ induces the expression of a number of genes which promote an anti-inflammatory state and tightly control the level of cGMP thus promoting responsiveness to endothelial derived NO. One of the PPARγ targets in smooth muscle, RhoBTB1 acts as a substrate adaptor for proteins to be ubiquitinated by the E3 ubiquitin ligase Cullin-3 and targeted for proteasomal degradation. One of these proteins, phosphodiesterase 5 (PDE5) is a target of the CUL3/RhoBTB1 pathway. PDE5 degrades cGMP to GMP and thus regulates the smooth muscle response to NO. Moreover, expression of RhoBTB1 under condition of RhoBTB1-deficiency reverses established arterial stiffness. In conclusion, the coordinated action of PPARγ in endothelium and smooth muscle is needed to maintain NO bioavailability and activity, and is an essential regulator of vasodilator/vasoconstrictor balance and regulates blood vessel structure and stiffness.