Fgl2deficiency causes neonatal death and cardiac dysfunction during embryonic and postnatal development in mice

Abstract

We hypothesized that cardiac dysfunction was responsible for the high perinatal lethality that we previously reported in fibrinogen-like protein 2 (Fgl2) knockout (KO) mice. We therefore used ultrasound biomicroscopy to assess left ventricular (LV) cardiac structure and function during development in Fgl2 KO and wild-type (WT) mice. The only deaths observed between embryonic day (E)8.5 (onset of heart beating) and postnatal day (P)28 (weaning) were within 3 days after birth, when 33% of Fgl2 KO pups died. Histopathology and Doppler assessments suggested that death was due to acute congestive cardiac failure without evidence of valvular or other obvious cardiac structural abnormalities. Heart rates in Fgl2 KO embryos were significantly reduced at E8.5 and E17.5, and irregular heart rhythms were significantly more common in Fgl2 KO (21/26) than WT (2/21) embryos at E13.5. Indexes of systolic and/or diastolic cardiac function were also abnormal in KO mice at E13.5 and E17.5, in postnatal mice studied at P1, and in KO mice surviving to P28. M-mode analysis showed no difference in LV diastolic chamber dimension, although posterior wall thickness was thinner at P7 and P28 in Fgl2 KO mice. We conclude that Fgl2 deficiency is not associated with obvious structural cardiac defects but is associated with a high incidence of neonatal death as well as contractile dysfunction and rhythm abnormalities during embryonic and postnatal development in mice.

Fibrinogen-like protein 2/fibroleukin prothrombinase contributes to tumor hypercoagulability via IL-2 and IFN-γ

“…The direct prothrombinase activity of fgl2 is implicated in the pathogenesis of several inflammatory disorders including fulminant hepatitis and severe hepatitis, alloand xeno-graft rejection [4,11,12] . Furthermore, its role is also evidenced in murine and human cytokine induced fetal loss [5,[13][14][15] and neonatal death from contractile dysfunction and rhythm abnormalities during embryonic and postnatal development [16] . The observations that neutralizing Abs to mfgl2 prevent both fibrin deposition and death from MHV-3 infection support its role as a coagulant [17] .…”

Novel Antibody against a Glutamic Acid-Rich Human Fibrinogen-Like Protein 2-Derived Peptide near Ser91 Inhibits hfgl2 Prothrombinase Activity

“…Several lines of in vivo evidences indicate that fgl2 serves as a multifunctional protein [11], [55]. In addition, it has been reported that fgl2 may be a more important procoagulant than tissue factor in xenograft acute vascular rejection characterized by fibrin deposition in situ or microvascular thrombosis [11], [56].…”

Micro-ultrasound for preclinical imaging

“…Micro-ultrasound has proved valuable for in vivo phenotyping of defects in cardiovascular function in embryos and during postnatal development caused by genetic alterations. Examples include evaluations of cardiac function in embryos with mutations in Fgl2, NFATc1, BMPRIA or Baf60c [50,[59][60][61]. Important cardiovascular events occur at birth when the placenta is lost from the circulation and a large increase in pulmonary blood flow occurs.…”

“…Further developmental changes in cardiac function occur in the weeks following birth and these can be monitored by micro-ultrasound (e.g. [50,53,54]). A growing area of research in developmental biology investigates how the early environment of the embryo and neonate influences long-term cardiovascular outcomes in adulthood (e.g.…”