Arterial remodelling relies on vascular smooth muscle cell (VSMC) proliferation, but its deregulation leads to intimal hyperplasia (IH). 3′,5′-cyclic adenosine monophosphate (cAMP) has been shown to modulate VSMC proliferation and intimal thickening. Phosphoinositide 3-kinase γ (PI3Kγ), a protein involved in immune processes underlying IH, regulates cAMP levels in cardiomyocytes, but their relationship has not been addressed in other cells of the cardiovascular system. In this Short Report, Muriel Laffargue, Damien Ramel and colleagues (Lupieri et al., 2020) demonstrate that the non-catalytic activity of PI3Kγ is required for VSMC proliferation in injury-induced IH. Bone marrow (BM) chimeras between wild-type (WT) and PI3Kγ-knockout (KO) and kinase-dead (KD) mice show that PI3Kγ is required in the vascular compartment to increase the neointimal area by VSMC proliferation after injury. Moreover, BM from WT mice introduced into KD mice induces VSMC proliferation, demonstrating that this process is independent of PI3Kγ's catalytic activity. Instead, PI3Kγ regulates VSMC proliferation by limiting intracellular cAMP levels, and this involves phosphodiesterase 4 (PDE4). Finally, blocking the A-kinase anchoring protein (AKAP) function of PI3Kγ suggests that its docking function regulates cAMP levels and consequently VSMC proliferation. Thus, this study uncovers a link between PI3Kγ and cAMP signalling and reveals a new non-catalytic function for PI3Kγ in VSMC biology.