Recent studies suggested a beneficial role of lymphatics in restoring heart function after cardiac injury 1 – 6 . Here we report that in mice lymphatics promote cardiac growth, repair and cardio-protection. We show that a lymphoangiocrine signal produced by lymphatic endothelial cells (LECs) controls cardiomyocyte (CM) proliferation and survival during heart development, improves neonatal cardiac regeneration and is cardioprotective after myocardial infarction (MI). Embryos devoid of LECs develop smaller hearts as a consequence of reduced CM proliferation and increased CM apoptosis. Culturing primary mouse CMs in LEC-conditioned media increases CM proliferation and survival, indicating that LECs produce lymphoangiocrine signals controlling CM homeostasis. Characterization of the LEC secretome identified Reelin as a key player responsible for such function. Moreover, we report that LEC-specific Reln -null embryos also develop smaller hearts, that Reelin is required for efficient heart repair and function following neonatal MI, and that cardiac delivery of REELIN using collagen patches improves adult heart function after MI through a cardioprotective effect. These results identify a lymphoangiocrine role of LECs during cardiac development and injury response, and Reelin as an important mediator of this function.

Despite the essential role of the lymphatic vasculature in tissue homeostasis and disease, knowledge of the organ-specific origins of lymphatic endothelial progenitor cells remains limited. The assumption that most murine embryonic lymphatic endothelial cells (LECs) are venous derived has recently been challenged. Here, we show that the embryonic dermal blood capillary plexus constitutes an additional, local source of LECs that contributes to the formation of the dermal lymphatic vascular network. We describe a novel mechanism whereby rare PROX1-positive endothelial cells exit the capillary plexus in a -dependent manner to establish discrete LEC clusters. As development proceeds, these clusters expand and further contribute to the growing lymphatic system. Lineage tracing and analyses of-deficient mice confirmed that these clusters are endothelial in origin. Furthermore, ectopic expression of in the vasculature increased the number of PROX1-positive progenitors within the capillary bed. Our work reveals a novel source of lymphatic endothelial progenitors employed during construction of the dermal lymphatic vasculature and demonstrates that the blood vasculature is likely to remain an ongoing source of LECs during organogenesis, raising the question of whether a similar mechanism operates during pathological lymphangiogenesis.

Background: Previously, whether the new SDF-1 receptor CXCR7 plays a role in macrophages linked to disease was unknown. Results: During macrophage differentiation, CXCR7 is up-regulated, detected in mouse atherosclerotic plaques, and mediates pro-phagocytic activity via JNK and p38 pathways. Conclusion: CXCR7 is a functional SDF-1 receptor in macrophages. Significance: Macrophage CXCR7 might be a new therapeutic target for atherosclerosis.

Macrophages, via activation of the Toll-like receptors (TLR4), play an important role in the pathogenesis of hypertension and associated end-organ damage. There is accumulating evidence to suggest a protective role of the angiotensin AT2 receptor (AT2R) in pathological conditions involving inflammation and tissue injury. We have recently shown that AT2R stimulation is renoprotective, in part, via increased anti-inflammatory interleukin-10 (IL-10) production in renal epithelial cells, however the role of AT2R in macrophage inflammatory behavior is not known. The present study was designed to investigate whether AT2R activation exerts an anti-inflammatory response in TLR4-induced inflammation. The anti-inflammatory mechanisms of AT2R agonist C21 (1 µmol/ml) pre-treatment on the cytokine profile of THP-1 macrophages after activation by LPS (1 µg/ml) was studied. The AT2R agonist dose-dependently attenuated LPS-induced TNF-α and IL-6 production but increased IL-10 production. IL-10 was critical for the anti-inflammatory effect of AT2R stimulation, since IL-10 neutralizing antibody dose-dependently abolished the AT2R–mediated decrease in TNF-α level. Further, the enhanced IL-10 levels were associated with a sustained, selective increase in phosphorylation of extracellular signal-regulated kinase (ERK1/2), but not p38 MAPK. Blocking the activation of ERK1/2 prior to C21 pre-treatment completely abrogated this increased IL-10 production in response to AT2R agonist C21, while there was a partial reduction in IL-10 levels on inhibition of p38. We conclude that AT2R stimulation exerts a novel anti-inflammatory response in THP-1 macrophages via enhanced IL-10 production as a result of sustained, selective ERK1/2 phosphorylation, and thus may have protective role in hypertension and associated tissue injury.