ABSTRACTPorphyromonas gingivalisis an important periodontal pathogen that can cause vascular injury and invade local tissues through the blood circulation, and its ability to evade leukocyte killing is critical to its distal colonization and survival. Transendothelial migration (TEM) is a series of that enable leukocytes to squeeze through endothelial barriers and migrate into local tissues to perform immune functions. Several studies have shown thatP. gingivalis-mediated endothelial damage initiates a series of proinflammatory signals that promote leukocyte adhesion. However, whetherP. gingivalisis involved in TEM and thus influences immune cell recruitment remains unknown. In our study, we found thatP. gingivalisgingipains could increase vascular permeability and promoteEscherichia colipenetration by downregulating platelet/endothelial cell adhesion molecule 1 (PECAM-1) expressionin vitro. Furthermore, we demonstrated that althoughP. gingivalisinfection promoted monocyte adhesion, the TEM capacity of monocytes was substantially impaired, which might be due to the reduced CD99 and CD99L2 expression on gingipain-stimulated endothelial cells and leukocytes. Mechanistically, gingipains mediate CD99 and CD99L2 downregulation, possibly through the inhibition of the phosphoinositide 3-kinase (PI3K)/Akt pathway. In addition, ourin vivomodel confirmed the role ofP. gingivalisin promoting vascular permeability and bacterial colonization in the liver, kidney, spleen, and lung and in downregulating PECAM-1, CD99, and CD99L2 expression in endothelial cells and leukocytes.IMPORTANCEP. gingivalisis associated with a variety of systemic diseases and colonizes in distal locations in the body. Here, we found thatP. gingivalisgingipains degrade PECAM-1 to promote bacterial penetration while simultaneously reducing leukocyte TEM capacity. A similar phenomenon was also observed in a mouse model. These findings establishedP. gingivalisgingipains as the key virulence factor in modulating the permeability of the vascular barrier and TEM processes, which may provide a new rationale for the distal colonization ofP. gingivalisand its associated systemic diseases.