Reassessing the role of PPARgamma in vascular effects of cannabinoids: A critical appraisal.

This focused review provides a critical narrative appraisal of the mechanisms underlying cannabinoid-induced vascular effects, with particular emphasis on cannabinoid receptor- and PPARgamma-independent pathways, as well as on ion channel modulation. Priority was given to studies providing mechanistic insights into vascular signaling pathways mediating the vasodilator effects of cannabinoids and commonly used PPARgamma ligands. The available experimental evidence supporting a role for PPARgamma in the vascular actions of cannabinoids is critically evaluated. Given the partially overlapping pharmacological profiles of cannabinoids and commonly used PPARgamma ligands, together with the lack of direct evidence demonstrating that PPARgamma itself, rather than off-target effects of its ligands, is responsible for vasodilation, the proposed role of PPARgamma in cannabinoid-induced vascular effects should be interpreted with caution. Definitive validation of PPARgamma involvement in the vascular effects of cannabinoids requires complementary approaches, including the use of genetic animal models, targeted manipulation of PPARgamma, and the use of highly selective ligands.