Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress.

Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. Consistent with data from obese, hypertensive humans, mice with an endothelial cell-specific deficiency in Panx3 had spontaneous systemic hypertension without obvious changes in channel function, as assessed by Ca2+ handling, ATP amounts, or Golgi luminal pH. Panx3 bound to Bcl6, and its absence reduced Bcl6 protein abundance, suggesting that the interaction with Panx3 stabilized Bcl6 by preventing its degradation. Panx3 deficiency was associated with increased expression of the gene encoding the H2O2-producing enzyme Nox4, which is normally repressed by Bcl6, resulting in H2O2-induced oxidative damage in the vasculature. Catalase rescued impaired vasodilation in mice lacking endothelial Panx3. Administration of a newly developed peptide to inhibit the Panx3-Bcl6 interaction recapitulated the increase in Nox4 expression and in blood pressure seen in mice with endothelial Panx3 deficiency. Panx3-Bcl6-Nox4 dysregulation occurred in obesity-related hypertension, but not when hypertension was induced in the absence of obesity. Our findings provide insight into a channel-independent role of Panx3 wherein its interaction with Bcl6 determines vascular oxidative state, particularly under the adverse conditions of obesity.

Physiological functions of caveolae in endothelium.

Endothelial caveolae are essential for a wide range of physiological processes and have emerged as key players in vascular biology. Our understanding of caveolar biology in endothelial cells has expanded dramatically since their discovery revealing critical roles in mechanosensation, signal transduction, eNOS regulation, lymphatic transport, and metabolic disease progression. Furthermore, caveolae are involved in the organization of membrane domains, regulation of membrane fluidity, and endocytosis which contribute to endothelial function and integrity. Additionally, recent advances highlight the impact of caveolae-mediated signaling pathways on vascular homeostasis and pathology. Together, the diverse roles of caveolae discussed here represent a breadth of cellular functions presenting caveolae as a defining feature of endothelial form and function. In light of these new insights, targeting caveolae may hold potential for the development of novel therapeutic strategies to treat a range of vascular diseases.