TY - JOUR
T1 - Abnormal sinoatrial node development resulting from disturbed vascular endothelial growth factor signaling
AU - Calkoen, Emmeline E.
AU - Vicente-Steijn, Rebecca
AU - Hahurij, Nathan D.
AU - van Munsteren, Conny J.
AU - Roest, Arno A. W.
AU - Deruiter, Marco C.
AU - Steendijk, Paul
AU - Schalij, Martin J.
AU - Gittenberger-de Groot, Adriana C.
AU - Blom, Nico A.
AU - Jongbloed, Monique R. M.
PY - 2015
Y1 - 2015
N2 - Background: Sinus node dysfunction is frequently observed in patients with congenital heart disease (CHD). Variants in the Vascular Endothelial Growth Factor-A (VEGF) pathway are associated with CHD. In Vegf(120/120) mice, over-expressing VEGF(120), a reduced sinoatrial node (SAN) volume was suggested. Aim of the study is to assess the effect of VEGF over-expression on SAN development and function. Methods: Heart rate was measured in Vegf(120/120) and wildtype (WT) embryos during high frequency ultrasound studies at embryonic day (E) 12.5, 14.5 and 17.5 and by optical mapping at E12.5. Morphology was studied with several antibodies. SAN volume estimations were performed, and qualitative-PCR was used to quantify expression of genes in SAN tissues of WT and Vegf(120/120) embryos. Results: Heart rate was reduced in Vegf(120/120) compared with WT embryos during embryonic echocardiography (52 +/- 17 versus 125 +/- 31 beats per minute (bpm) at E12.5, p <0.001; 123 +/- 37 vs 160 +/- 29 bmp at E14.5, p = 0.024; and 177 +/- 30 vs 217 +/- 34 bmp, at E17.5 p = 0.017) and optical mapping (81 +/- 5 vs 116 +/- 8 bpm at E12.5; p = 0.003). The SAN of mutant embryos was smaller and more vascularized, and showed increased expression of the fast conducting gap junction protein, Connexin43. Conclusions: Over-expression of VEGF(120) results in reduced heart rate and a smaller, less compact and hypervascularized SAN with increased expression of Connexin43. This indicates that VEGF is necessary for normal SAN development and function. (C) 2014 Elsevier Ireland Ltd. All rights reserved
AB - Background: Sinus node dysfunction is frequently observed in patients with congenital heart disease (CHD). Variants in the Vascular Endothelial Growth Factor-A (VEGF) pathway are associated with CHD. In Vegf(120/120) mice, over-expressing VEGF(120), a reduced sinoatrial node (SAN) volume was suggested. Aim of the study is to assess the effect of VEGF over-expression on SAN development and function. Methods: Heart rate was measured in Vegf(120/120) and wildtype (WT) embryos during high frequency ultrasound studies at embryonic day (E) 12.5, 14.5 and 17.5 and by optical mapping at E12.5. Morphology was studied with several antibodies. SAN volume estimations were performed, and qualitative-PCR was used to quantify expression of genes in SAN tissues of WT and Vegf(120/120) embryos. Results: Heart rate was reduced in Vegf(120/120) compared with WT embryos during embryonic echocardiography (52 +/- 17 versus 125 +/- 31 beats per minute (bpm) at E12.5, p <0.001; 123 +/- 37 vs 160 +/- 29 bmp at E14.5, p = 0.024; and 177 +/- 30 vs 217 +/- 34 bmp, at E17.5 p = 0.017) and optical mapping (81 +/- 5 vs 116 +/- 8 bpm at E12.5; p = 0.003). The SAN of mutant embryos was smaller and more vascularized, and showed increased expression of the fast conducting gap junction protein, Connexin43. Conclusions: Over-expression of VEGF(120) results in reduced heart rate and a smaller, less compact and hypervascularized SAN with increased expression of Connexin43. This indicates that VEGF is necessary for normal SAN development and function. (C) 2014 Elsevier Ireland Ltd. All rights reserved
U2 - https://doi.org/10.1016/j.ijcard.2014.12.006
DO - https://doi.org/10.1016/j.ijcard.2014.12.006
M3 - Article
C2 - 25700200
SN - 0167-5273
VL - 183
SP - 249
EP - 257
JO - International journal of cardiology
JF - International journal of cardiology
ER -