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Hypoxia regulates placental angiogenesis via alternatively activated macrophages
Author(s) -
Zhao Hui,
Kalish Flora S.,
Wong Ronald J.,
Stevenson David K.
Publication year - 2018
Publication title -
american journal of reproductive immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.071
H-Index - 97
eISSN - 1600-0897
pISSN - 1046-7408
DOI - 10.1111/aji.12989
Subject(s) - angiogenesis , endocrinology , medicine , sod2 , hypoxia (environmental) , biology , placental growth factor , gpx1 , estrogen , vascular endothelial growth factor , vascular endothelial growth factor a , mmp2 , chemistry , andrology , glutathione peroxidase , superoxide dismutase , oxidative stress , organic chemistry , oxygen , vegf receptors , cancer , metastasis
Problem Uterine and placental macrophages play critical roles in maintaining a normal pregnancy. The majority of these macrophages are believed to be alternatively activated macrophages (M2). Method of Study Mouse bone marrow cells were differentiated into macrophages and polarized to M2 in vitro by treatment with IL ‐4 [M2a] or IL ‐10 [M2c] and M1 with LPS / IFN ‐γ as controls. Macrophage subtypes were confirmed by surface markers and characterized by gene expression profiles. Results Compared to M1, M2 showed strong pro‐angiogenic activity by expressing higher mRNA for angiogenic‐associated factors (Cxcl12, Vegfa, Pl GF , Mmp2). M2c produced the highest levels of Pl GF , Mmp2, and Cxcr4. To mimic the normal placental microenvironment, M2 were exposed to hypoxia and sex hormones (progesterone, estrogen). In both M2c and M2a, severe hypoxic (1%‐3% O 2 ) exposure significantly suppressed Pl GF , Cxcl12, and Mmp2 mRNA , but not Vegfa, compared to normoxia (21% O 2 ) or physiological hypoxia (5% O 2 ). mRNA expression returned to normal when hypoxic cells were returned to normoxia. Hypoxia (1%) reduced antioxidant levels in M2 and re‐exposure to normoxia significantly increased superoxide dismutase (Sod1, Sod2) and heme oxygenase‐1 ( HO ‐1) levels in M2a, and only glutathione peroxidase (Gpx1, Gpx3, Gpx4) in M2c. However, progesterone and estrogen treatment had minimal effects on angiogenic factor expression in M2. Conclusion M2, particularly M2c, displayed strong pro‐angiogenic potential, which decreased under severe hypoxia such as in early pregnancy. Thus, conditions that alter the placental oxygen microenvironment or macrophage response in early pregnancy might cause aberrant angiogenesis and vascular remodeling, and lead to abnormal placental vascular development.