Abstract
Dysfunctional lymphatic networks can lead to lymphatic diseases such as lymphedema as well as aggravate cardiovascular diseases such as atherosclerosis and hypertension. Some primary lymphedema patients have mutations in the
Neuropilin 2
(
NRP2
) gene, which encodes a transmembrane receptor that acts with VEGFR3 for the ligands VEGF-C and VEGF-D. Nrp2 has been shown to be a key regulator of lymphatic vessel development in the neonate as global
Nrp2
-deficient mice suffer from reduced lymphatic density. However, Nrp2 protein expression is dramatically downregulated after birth and its role in adult lymphangiogenesis or its relevance in lymphedema is less clear. Our hypothesis is that Nrp2 expression is necessary for optimal lymphangiogenesis and proper lymphatic drainage function in the adult, and that loss of
Nrp2
, either genetically or transcriptionally via down-regulation by specific transcription factors, may worsen lymphedema. In acute and chronic mouse inflammation models, we found that loss of
Nrp2
specifically in the lymphatic endothelium (
prox1-cre
ERT2
;Nrp2
f/f
) resulted in prolonged swelling and reduced lymphatic drainage compared to control mice. Using the VEGFC-induced corneal lymphangiogenesis model and the tail wound-induced secondary lymphedema model, LEC-Nrp2-iKO mice showed diminished lymphangiogenesis and reduced lymphatic drainage compared to littermate controls. Furthermore, primary mouse dermal LEC isolated from Nrp2-iKO mice reveal suppressed VEGFR3 activation, signaling, and proliferation following VEGF-C stimulation, compared to LEC isolated from control mice. Collectively, our results identify Nrp2 as a critical mediator of lymphangiogenesis and homeostatic lymphatic drainage function in adult tissues.