| First Author | Petkova M | Year | 2023 |
| Journal | J Exp Med | Volume | 220 |
| Issue | 4 | PubMed ID | 36688917 |
| Mgi Jnum | J:341130 | Mgi Id | MGI:7437332 |
| Doi | 10.1084/jem.20220741 | Citation | Petkova M, et al. (2023) Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation. J Exp Med 220(4) |
| abstractText | Oncogenic mutations in PIK3CA, encoding p110alpha-PI3K, are a common cause of venous and lymphatic malformations. Vessel type-specific disease pathogenesis is poorly understood, hampering development of efficient therapies. Here, we reveal a new immune-interacting subtype of Ptx3-positive dermal lymphatic capillary endothelial cells (iLECs) that recruit pro-lymphangiogenic macrophages to promote progressive lymphatic overgrowth. Mouse model of Pik3caH1047R-driven vascular malformations showed that proliferation was induced in both venous and lymphatic ECs but sustained selectively in LECs of advanced lesions. Single-cell transcriptomics identified the iLEC population, residing at lymphatic capillary terminals of normal vasculature, that was expanded in Pik3caH1047R mice. Expression of pro-inflammatory genes, including monocyte/macrophage chemokine Ccl2, in Pik3caH1047R-iLECs was associated with recruitment of VEGF-C-producing macrophages. Macrophage depletion, CCL2 blockade, or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. Thus, targeting the paracrine crosstalk involving iLECs and macrophages provides a new therapeutic opportunity for lymphatic malformations. Identification of iLECs further indicates that peripheral lymphatic vessels not only respond to but also actively orchestrate inflammatory processes. |
