Placental growth factor deficiency is associated with impaired cerebral vascular development in mice

被引:56
|
作者
Luna, Rayana Leal [1 ,2 ]
Kay, Vanessa R. [1 ]
Raetsep, Matthew T. [1 ]
Khalaj, Kasra [1 ]
Bidarimath, Mallikarjun [1 ]
Peterson, Nichole [1 ]
Carmeliet, Peter [3 ]
Jin, Albert [1 ]
Croy, B. Anne [1 ]
机构
[1] Queens Univ, Dept Biomed & Mol Sci, Kingston, ON K7L 3N6, Canada
[2] Fed Univ Pernambuco UFPE, BR-50670901 Recife, PE, Brazil
[3] Univ Leuven, Dept Oncol, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, Leuven, Belgium
基金
加拿大自然科学与工程研究理事会; 加拿大健康研究院;
关键词
cerebral vessels; circle of Willis; fetal development; PGF; pre-eclampsia; stroke; EXPRESSION; GENDER;
D O I
10.1093/molehr/gav069
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
STUDY HYPOTHESIS: Placental growth factor (PGF) is expressed in the developing mousebrain and contributes to vascularization and vessel patterning. STUDY FINDING: PGF is dynamically expressed in fetal mouse brain, particularly forebrain, and is essential for normal cerebrovascular development. WHAT IS KNOWN ALREADY: PGF rises in maternal plasma over normal human and mouse pregnancy but is low in many women with the acute onset hypertensive syndrome, pre-eclampsia (PE). Little is known about the expression of PGF in the fetus during PE. Pgf -/- mice appear normal but recently cerebral vascular defects were documented in adult Pgf(-/-) mice. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: Here, temporal-spatial expression of PGF is mapped in normal fetal mouse brains and cerebral vasculature development is compared between normal and congenic Pgf(-/-) fetuses to assess the actions of PGF during cerebrovascular development. Pgf/PGF, Vegfa/VEGF, Vegf receptor (Vegfr) 1 and Vegfr2 expression were examined in the brains of embryonic day (E) 12.5, 14.5, 16.5 and 18.5 C57BL/6 (B6) mice using quantitative PCR and immunohistochemistry. The cerebral vasculature was compared between Pgf(-/-) and B6 embryonic and adult brains using whole mount techniques. Vulnerability to cerebral ischemia was investigated using a left common carotid ligation assay. MAIN RESULTS AND THE ROLE OF CHANCE: Pgf/PGF and Vegfr1 are highly expressed in E12.5-14.5 forebrain relative to VEGF and Vegfr2. Vegfa/VEGF is relatively more abundant in hindbrain (HB). PGF and VEGF expression were similar in midbrain. Delayed HB vascularization was seen at E10.5 and 11.5 in Pgf(-/-) brains. At E14.5, Pgf(-/-) circle of Willis showed unilateral hypoplasia and fewer collateral vessels, defects that persisted post-natally. Functionally, adult Pgf(-/-) mice experienced cerebral ischemia after left common carotid arterial occlusion while B6 mice did not. LIMITATIONS, REASONS FOR CAUTION: Since Pgf(-/-) mice were used, consequences of complete absence of maternal and fetal PGF were defined. Therefore, the effects of maternal versus fetal PGF deficiency on cerebrovascular development cannot be separated. However, as PGF was strongly expressed in the developing brain at all timepoints, we suggest that local PGF has a more important role than distant maternal or placental sources. Full PGF loss is not expected in PE pregnancies, predicting that the effects of PGF deficiency identified in this model will be more severe than any effects in PE-offspring. WIDER IMPLICATIONS OF THE FINDINGS: These studies provoke the question of whether PGF expression is decreased and cerebral vascular maldevelopment occurs in fetuses who experience a preeclamptic gestation. These individuals have already been reported to have elevated risk for stroke and cognitive impairments. LARGE SCALE DATA: N/A. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by awards from the Natural Sciences and Engineering Research Council, the Canada Research Chairs Program and the Canadian Foundation for Innovation to B.A.C. and by training awards from the Universidade Federal de Pernambuco and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil to R.L.L.; Queen's University to V.R.K. and the Canadian Institutes of Health Research to M.T.R. The work of P.C. is supported by the Belgian Science Policy BELSPO-IUAP7/03, Structural funding by the Flemish Government-Methusalem funding, and the Flemish Science Fund-FWO grants. There were no competing interests.
引用
收藏
页码:130 / 142
页数:13
相关论文
共 50 条
  • [1] PLACENTAL GROWTH FACTOR (PGF) IN CEREBRAL VASCULAR DEVELOPMENT
    Luna, Rayana Leal
    Kay, Vanessa R.
    Raetsep, Matthew T.
    Khalaj, Kasra
    Bidarimath, Mallikarjun
    Peterson, Nicki
    Jin, Albert
    Croy, Anne B.
    PLACENTA, 2015, 36 (04) : 506 - 506
  • [2] Impaired adipose tissue development in mice with inactivation of placental growth factor function
    Lijnen, H. Roger
    Christiaens, Valerie
    Scroyen, Ilse
    Voros, Gabor
    Tjwa, Marc
    Carmeliet, Peter
    Collen, Desire
    DIABETES, 2006, 55 (10) : 2698 - 2704
  • [3] Impaired adipose tissue development in mice with inactivation of placental growth factor function
    Lijnen, H.
    Christiaens, V.
    Scroyen, I.
    Voros, G.
    Tjwa, M.
    Carmeliet, P.
    Collen, D.
    JOURNAL OF THROMBOSIS AND HAEMOSTASIS, 2006, 4 : 154 - 154
  • [4] Impaired wound healing in mice lacking placental growth factor
    Carmeliet, P
    DiPalma, T
    Barra, A
    Moons, L
    Oosthuyze, B
    Brusselmans, K
    Collen, D
    Persico, G
    THROMBOSIS AND HAEMOSTASIS, 1997, : PD642 - PD642
  • [5] Impaired collateral vessel development associated with reduced expression of vascular endothelial growth factor in ApoE-/- mice
    Couffinhal, T
    Silver, M
    Kearney, M
    Sullivan, A
    Witzenbichler, B
    Magner, M
    Annex, B
    Peters, K
    Isner, JM
    CIRCULATION, 1999, 99 (24) : 3188 - 3198
  • [7] Prepregnancy Vitamin D Deficiency and Placental Growth and Development in Mice
    Gernand, Alison D.
    Cantorna, Margherita T.
    Diaz, Francisco J.
    Snyder, Lyndsay M.
    Hester, James M.
    Vasudevan, Sreelakshmi
    Kamat, Manasi M.
    Ott, Troy L.
    FASEB JOURNAL, 2016, 30
  • [8] Effects of placental growth factor deficiency on behavior, neuroanatomy, and cerebrovasculature of mice
    Kay, Vanessa R.
    Ratsep, Matthew T.
    Cahill, Lindsay S.
    Hickman, Andrew F.
    Zavan, Bruno
    Newport, Margaret E.
    Ellegood, Jacob
    Laliberte, Christine L.
    Reynolds, James N.
    Carmeliet, Peter
    Tayade, Chandrakant
    Sled, John G.
    Croy, B. Anne
    PHYSIOLOGICAL GENOMICS, 2018, 50 (10) : 862 - 875
  • [9] Influences of Placental Growth Factor on Mouse Retinal Vascular Development
    Kay, Vanessa R.
    Tayade, Chandrakant
    Carmeliet, Peter
    Croy, B. Anne
    DEVELOPMENTAL DYNAMICS, 2017, 246 (09) : 700 - 712
  • [10] Are Altered Expression of Vascular Endothelial Growth Factor and Placental Growth Factor Associated with Placental Angiogenesis in Recurrent Pregnancy Loss?
    Sultana, Shehnaz
    Devi, M. R. Renjini
    Rathod, Mahesh Kumar
    Reddy, Penagaluru Pardhanandana
    Ananthapur, Venkateshwari
    INDIAN JOURNAL OF CLINICAL BIOCHEMISTRY, 2024, 39 (03) : 387 - 391