Immune-interacting lymphatic endothelial subtype at capillary terminals drives lymphatic malformation

Milena Petkova, Marle Kraft, Simon Stritt, Ines Martinez-Corral, Henrik Ortsäter, Michael Vanlandewijck, Bojana Jakic, Eulàlia Baselga, Sandra D. Castillo, Mariona Graupera, Christer Betsholtz, Taija Mäkinen

Research output: Contribution to journalArticleScientificpeer-review

Abstract

Oncogenic mutations in PIK3CA, encoding p110α-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 prolymphangiogenic 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, inPik3caH1047R-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.

Original languageEnglish
Article numbere20220741
JournalJournal of Experimental Medicine
Volume220
Issue number4
ISSN0022-1007
DOIs
Publication statusPublished - 2023
Externally publishedYes
MoE publication typeA1 Journal article-refereed

Bibliographical note

Publisher Copyright:
© 2023 Petkova et al.

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