Vascular injury associated with PTCA involves endothelial denudation and stretching of the vascular wall, and can lead to restenosis, characterized by neointima formation and constrictive inward remodeling mediated by VSMC migration, proliferation and extracellular matrix deposition. Incidence of restenosis has been reduced by use of drug-eluting stents (DES); however, a significant complication associated with DES use is in-stent thrombosis, primarily caused by lack of endothelial regeneration. Torelli et al. demonstrated that the p85 regulatory subunit of phosphoinositol 3-kinase (PI3K) phosphorylated on the protein kinase A (PKA)-dependent Serine 83 (Ser83) significantly reduced neointima formation, but did not prevent endothelial regeneration following rat carotid balloon injury, thus identifying PKA-activated PI3K signaling as a potential target for development of DES which would allow for rendothelialization, and thus eliminate in-stent thrombosis. However, the regulation of the PKA-activated PI3K signaling pathway in endothelial vs. vascular smooth muscle cells in response to vascular injury in vivo remains to be investigated. Several factors may modulate the PKA-activated PI3K signaling pathway, including the interplay between cAMP, cGMP and their respective PDEs, coupling of different p85 regulatory to different p110 catalytic subunits of PI3K, as well as their divergent regulation by factors released in response to vascular injury, including PDGF, which may result in altered downstream signaling. Finally, modulation of PKA-activated PI3K signaling by risk factors for coronary artery disease and coronary intervention, such as type II diabetes, hypertension, obesity, dyslipidemia or the combined metabolic syndrome should be evaluated in future studies.