Endothelial‐Smooth Muscle Cell Interactions in a Shear‐Exposed Intimal Hyperplasia on‐a‐Dish Model to Evaluate Therapeutic Strategies

Abstract

Intimal hyperplasia (IH) represents a major challenge following cardiovascular interventions. While mechanisms are poorly understood, the inefficient preventive methods incentivize the search for novel therapies. A vessel‐on‐a‐dish platform is presented, consisting of direct‐contact cocultures with human primary endothelial cells (ECs) and smooth muscle cells (SMCs) exposed to both laminar pulsatile and disturbed flow on an orbital shaker. With contractile SMCs sitting below a confluent EC layer, a model that successfully replicates the architecture of a quiescent vessel wall is created. In the novel IH model, ECs are seeded on synthetic SMCs at low density, mimicking reendothelization after vascular injury. Over 3 days of coculture, ECs transition from a network conformation to confluent 2D islands, as promoted by pulsatile flow, resulting in a “defected” EC monolayer. In defected regions, SMCs incorporated plasma fibronectin into fibers, increased proliferation, and formed multilayers, similarly to IH in vivo. These phenomena are inhibited under confluent EC layers, supporting therapeutic approaches that focus on endothelial regeneration rather than inhibiting proliferation, as illustrated in a proof‐of‐concept experiment with Paclitaxel. Thus, this in vitro system offers a new tool to study EC‐SMC communication in IH pathophysiology, while providing an easy‐to‐use translational disease model platform for low‐cost and high‐content therapeutic development.

Polydopamine (PDA) coatings with endothelial vascular growth factor (VEGF) immobilization inhibiting neointimal formation post zinc (zn) wire implantation in rat aortas

“…This observation is probably due to the quenching of the RBITC that was used to label the BSA. On the other hand, since endothelial cells can efficiently inhibit thrombosis and neointimal formation [ 32 , 33 ], we thus chose VEGF as ad-layers to promote attachment, spreading, proliferation, and phenotype maintenance of ECs on Zn surfaces. Indeed, ECs had optimal behaviors on the PDA and VEGF-coated Zn surfaces (Figs.…”

Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation

“…Neointimal hyperplasia (NIH) of graft and anastomotic sites, which profoundly impacts the long-term patency and outcomes of vascular conduits after CABG, primarily unfolds via three signi cant mechanisms: (1) hyper-acute stage involving endothelial damage and platelet accumulation; (2) acute stage involving endothelial dysfunction and in ammation; and (3) chronic stage involving VSMC proliferation and migration, ECM synthesis, and NI formation [9,46,47]. Sirolimus and rosuvastatin are recognized for their effectiveness in preventing NIH [17,48] and represent potential pharmacological agents to improve long-term patency following CABG.…”

Polydopamine (PDA) coatings with endothelial vascular growth factor (VEGF) immobilization inhibiting neointimal formation post zinc (Zn) wire implantation in rat aortas

“…This observation is probably due to the quenching of the RBITC that was used to label the BSA. On the other hand, since endothelial cells can e ciently inhibit thrombosis and neointimal formation [31,32], we thus chose VEGF as ad-layers to promote attachment, spreading, proliferation, and phenotype maintenance of ECs on Zn surfaces. Indeed, ECs had optimal behaviors on the PDA and VEGF-coated Zn surfaces (Figs.…”