Vascular smooth muscle cells (VSMCs) can dynamically change their phenotype between con-tractile and synthetic forms in response to environmental stress, which is pivotal in maintaining vascular homeostasis and mediating pathological remodeling of blood vessels. We previously reported that suppression of canonical transient receptor potential 6 (TRPC6) activation by Ca2+ entry sustains VSMCs contractile phenotype and promotes the blood flow recovery after hindlimb ischemia. In contrast, a metal biomolecule, Zn2+ mobilized by TRPC6 channel activation, is revealed to exert a potential beneficial effect on cardiac contractility. However, the role of TRPC6-mediated Zn²⁺ influx in VSMCs phenotypic switching is still unknown. Here we found the involvement of Zn²⁺ influx through TRPC6 channels in TGFβ-induced contractile differentiation of rat aorta-origin smooth muscle cells (RAoSMCs). Using wild type (WT)- and Zn2+ permeation-dead TRPC6 (KYD) mutant-expressing RAoSMCs, we revealed that pharmacological TRPC6 activation by PPZ2 enhanced the intracellular Zn2+ amounts which overcame TGFβ-induced intracellular Zn2+ depletion and contractile differentiation in RAoSMCs (WT), but failed in RAoSMCs (KYD). There is no significant difference in TRPC6 currents of both RAoSMCs (WT) and (KYD) cells with or without TGFβ stimulation. In addition, PPZ2 attenuated the progression of vascular remodeling caused by chronic angiotensin II treatment in mice. These data suggest that Zn2+ influx through TRPC6 channels will be a therapeutic potential for vascular diseases characterized by maladaptive phenotypic switching.