Downregulation of Lymphatic Vessel Formation Factors in PGF2α-induced Luteolysis in the Cow

Prostaglandin F-2 alpha (PGF(2 alpha)) induces luteolysis in cows and causes infiltration of immune cells, which resembles inflammatory immune response. Since the general immune response is mediated by the lymphatic system, we hypothesized that luteolysis is associated with generation of an immune response that involves lymphatic vessels in the bovine corpus luteum (CL). The CL was obtained from Holstein cows at the mid-luteal phase (days 10-12, ovulation = day 0) by ovariectomy at various time points after PGF(2 alpha) injection. Lymphatic endothelial cell (LyEC) marker, endothelial hyaluronan receptor 1 (LYVE1), levels decreased significantly 12 h after PGF(2 alpha) injection. Podoplanin, another LyEC marker, decreased from 15 min after PGF(2 alpha) injection. PGF(2 alpha) also diminished mRNA expression of lymphangiogenic factors, such as vascular endothelial growth factor (VEGF) C, VEGFD and VEGF receptor 3 (VEGFR3). During PGF(2 alpha)-induced luteolysis, the levels of mRNA expression of tumor necrosis factor alpha (TNF alpha; the major pro-inflammatory cytoldne) and chemokine (C-X-C motif) ligand 1 (neutrophil chemokine) were increased. On the other hand, chemokine (C-C motif) ligand 21, which regulates outflow of immune cells from tissues via the lymphatic vessels during an immune response, was decreased. This study demonstrated that the lymphatic network in the CL is disrupted during luteolysis and suggests that during luteolysis, immune cells can induce a local immune response in the CL without using the lymphatic vessels.