Angiopoietin-2 promotes inflammatory lymphangiogenesis and its effect can be blocked by the specific inhibitor L1-10

Abstract

Angiopoietin (Ang)-2, a ligand of the receptor tyrosine kinase Tie2, is known to be involved in the regulation of embryonic lymphangiogenesis. However, the role of Ang-2 in postnatal pathological lymphangiogenesis, such as inflammation, is largely unknown. We used a combination of imaging, molecular, and cellular approaches to investigate whether Ang-2 is involved in inflammatory lymphangiogenesis. We observed strong and continuous expression of Ang-2 on newly generated lymphatic vessels for 2 wk in sutured corneas of BALB/c mice. This expression was concurrent with an increased number of lymphatic vessels. TNF-α expression also increased, with peak TNF-α expression occurring before peak Ang-2 expression was reached. In vitro experiments showed that TNF-α stimulates Ang-2 and Tie2 and ICAM-1 expression on human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BECs). Ang-2 alone did not affect the biological behavior of LECs, whereas Ang-2 combined with TNF-α significantly promoted the proliferation of LECs but not BECs. In mouse models, blockade of Ang-2 with L1-10, an Ang-2-specific inhibitor, significantly inhibited lymphangiogenesis but promoted angiogenesis. These results clearly indicate that Ang-2 acts as a crucial regulator of inflammatory lymphangiogenesis by sensitizing the lymphatic vasculature to inflammatory stimuli, thereby directly promoting lymphangiogenesis. The involvement of Ang-2 in inflammatory lymphangiogenesis provides a strong rationale for the exploitation of anti-Ang-2 treatment in the prevention and treatment of tumor metastasis and transplant rejection.

Regulation and implications of inflammatory lymphangiogenesis

“…Lymphangiogenesis suppression improves the survival of experimentally transplanted pancreatic islet cells [75] and cornea [80]. Recently, angiopoietin-2 suppression has been suggested as a candidate method to prevent rejection [81]. Temporary selective inhibition of lymphangiogenesis before transplantation might help prevent early postoperative access of inflammatory cells to the lymphatic system and improve overall graft survival [76].…”

The interaction between fluid status and angiopoietin-2 in adverse renal outcomes of chronic kidney disease

“…Angpt2 not only promote a significant increase in neutrophil accumulation, migration and adherence to the endothelium [3,28], but also Angpt2 boosts vascular leakage [3] and sensitizes the lymphatic vasculature to inflammatory stimuli [29]. On the other hand, fluid overload has been significantly associated with activation of malnutrition-inflammation process in CKD population [19], and it is difficult to differentiate whether inflammation is a cause or consequence of fluid overload.…”

Blockade of Endothelial Growth Factor, Angiopoietin-2, Reduces Indices of Ards and Mortality in Mice Resulting from the Dual-Insults of Hemorrhagic Shock and Sepsis

“…Fc fusion protein Ang-2 specific inhibitor/L1-10 was delivered sub-cutaneously (s.c.) in PBS, 4mg/kg body weight (~120ug/mouse/treatment) as described by Oliner et al, Tressel et al, and Yan et al (22–24). For the experiments reported here, L1-10 was administered immediately following hemorrhage resuscitation or immediately following CLP or at both time points.…”