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 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.
FTY720 increases tone and contractile responses to depolarization in gastric fundus smooth muscle by triggering calcium entry and calcium sensitization in a S1P receptor-dependent manner. Taken together, the experimental results presented in this work suggest that FTY720 may increase gastric tone and contractility in patients.
Vascular malformations are congenital, chronically debilitating diseases. Somatic oncogenic mutations in PIK3CA, encoding p110α-PI3K, specifically cause venous and lymphatic malformations (LM), yet the basis of vessel type-restricted disease manifestation is unknown. Here we report endothelial subtype-specific responses to the common causative Pik3caH1047R mutation, and reveal a new immunoregulatory subtype of dermal lymphatic capillary endothelial cells (iLECs) as a driver of LM pathology. Mouse model of Pik3caH1047R-driven vascular malformations showed that cell proliferation was a common early response of venous and lymphatic ECs to oncogenic Pik3ca, but sustained selectively in LECs of advanced lesions. Lymphatic overgrowth was associated with increased pro-inflammatory cytokine levels and pro-lymphangiogenic myeloid cell infiltrate. Single-cell transcriptomics revealed a new LEC subtype at capillary terminals, characterized by the expression of immunoregulatory genes. Selective expansion and activation of iLECs in the Pik3caH1047R mice was evidenced by proliferation and upregulation of pro-inflammatory genes. Importantly, macrophage depletion or anti-inflammatory COX-2 inhibition limited Pik3caH1047R-driven lymphangiogenesis. This provides a therapeutic target for LM and suggests a paracrine crosstalk in which LEC-autonomous oncogenic Pik3ca signaling induces immune activation that in turn sustains pathological lymphangiogenesis. Identification of iLECs indicates that peripheral lymphatic vessels not only respond to inflammation but also actively orchestrate the immune response.
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