Smoking increases Sema4D expression on CD8+ T cells in mouse models, leading to binding of Sema4D with PlexinB1 on choroidal pericytes, resulting in pericyte activation, vascular instability, and increased choroidal neovascularization lesion volume, as evidenced by reduced lesion volume in Sema4D-deficient mice.

Smoking causes immune cells called CD8+ T cells to produce more Sema4D protein. These cells travel to damaged blood vessels in the eye because the vessel support cells release a chemical that pulls them in. Once there, the Sema4D on the immune cells locks onto a receptor called PlexinB1 on the vessel support cells. This triggers a chain reaction inside the support cells that makes them contract, produce stiff scar-like material, and change into a different cell type. These changes break the normal support structure around the blood vessels, causing leaks and allowing abnormal new blood vessels to grow uncontrollably.