A role of platelet C-type lectin-like receptor-2 and its ligand podoplanin in vascular biology.

Platelets are essential for hemostasis and are also vital in lymphatic and lung development and the maintenance of vascular integrity. Platelet activation receptor C-type lectin-like receptor 2 (CLEC-2) and its endogenous ligand podoplanin (PDPN) in lymphatic endothelial cells (LECs) and other cells regulate these processes. This review aims to comprehensively summarize the roles of platelet CLEC-2 and PDPN. This review also focuses on discussing the underlying mechanisms by which platelet CLEC-2 and PDPN mediate blood/lymphatic separation. CLEC-2/PDPN-induced platelet activation in the primary lymph sacs, developmental lymphovenous junctions, neonatal mesentery, and the site of tumor lymphangiogenesis prevents blood/lymphatic vessel misconnection. Further, CLEC-2/PDPN-induced platelet activation is essential for lung development. Mice deficient in CLEC-2 or PDPN show blood-filled lymphatics, lung malformations, and cerebrovascular abnormalities. CLEC-2 deletion in steady-state adult mice did not result in blood/lymphatic vessel mixing. In adulthood, CLEC-2 maintains vascular integrity and that of high endothelial venules in lymph nodes. CLEC-2 deletion in adulthood results in hemorrhage under inflammatory conditions, and hemolymph nodes. The platelet CLEC-2/LEC PDPN interaction prevents blood/lymphatic vessel mixing at active remodeling sites of the blood/lymphatic system, but not in steady-state adult mice. This interaction also regulates vascular integrity when vascular permeability increases before and after birth.

Suzuki-Inoue K ，Tsukiji N 《-》

Platelet activation receptor CLEC-2 regulates blood/lymphatic vessel separation by inhibiting proliferation, migration, and tube formation of lymphatic endothelial cells.

Osada M ，Inoue O ，Ding G ，Shirai T ，Ichise H ，Hirayama K ，Takano K ，Yatomi Y ，Hirashima M ，Fujii H ，Suzuki-Inoue K ，Ozaki Y ... -  《-》

Physiologic and pathophysiologic roles of interaction between C-type lectin-like receptor 2 and podoplanin: partners from in utero to adulthood.

A platelet activation receptor, C-type lectin-like receptor 2 (CLEC-2), has been identified as a receptor for a platelet-activating snake venom, rhodocytin. CLEC-2 protein is highly expressed in platelets/megakaryocytes, and at lower levels in liver Kupffer cells. Recently, podoplanin has been revealed as an endogenous ligand for CLEC-2. Podoplanin is expressed in certain types of tumor cells, fibroblastic reticular cells (FRCs) in lymph nodes, kidney podocytes, and lymphatic endothelial cells, but not in vascular endothelial cells. CLEC-2 in platelets cannot have access to podoplanin under normal conditions, but they interact with each other under pathologic conditions or during developmental stages, and play various pathophysiologic roles. CLEC-2 facilitates hematogenous metastasis of podoplanin-expressing tumors. During development, the interaction between CLEC-2 and podoplanin in lymphatic endothelial cells or neuroepithelial cells facilitates blood-lymphatic vessel separation and cerebrovascular patterning and integrity, respectively. In adulthood, platelet CLEC-2 binding to FRCs is crucial for maintenance of the integrity of high endothelial venules in lymph nodes. Podoplanin-expressing FRC-like cells have recently been identified in the bone marrow, and facilitate megakaryocyte proliferation and proplatelet formation by binding to megakaryocyte CLEC-2. Podoplanin is inducibly expressed in liver monocytes and keratinocytes during Salmonella infection and wound healing, and regulates thrombus formation in the liver and controlled wound healing, respectively. By binding to unknown ligands, platelet CLEC-2 regulates the maintenance of vascular integrity during inflammation, thrombus stability under flow, and maintenance of quiescence of hematopoietic stem cells. Podoplanin is expressed in various cells, and additional roles of the CLEC-2-podoplanin interaction will be revealed in the future.

Suzuki-Inoue K ，Osada M ，Ozaki Y 《-》

Podoplanin maintains high endothelial venule integrity by interacting with platelet CLEC-2.

Herzog BH ，Fu J ，Wilson SJ ，Hess PR ，Sen A ，McDaniel JM ，Pan Y ，Sheng M ，Yago T ，Silasi-Mansat R ，McGee S ，May F ，Nieswandt B ，Morris AJ ，Lupu F ，Coughlin SR ，McEver RP ，Chen H ，Kahn ML ，Xia L ... -  《-》

[A role of the platelet receptor CLEC-2 in lymphangiogenesis and its clinical application].

Osada M ，Suzuki-Inoue K ，Inoue O ，Ozaki Y ... -  《-》