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Abstract

Abstract

Hemodynamic forces play an essential role in driving the morphogenesis of the embryonic heart and its valves. We previously found that genes that regulate heart morphogenesis like BMP2 and VEGFA, have hemodynamically specific patternings. However, how mechanical signals like wall shear stress (WSS) affect these expression levels to regulate heart morphogenesis is not fully understood. A detailed understanding of the hemodynamic environment and gene expression patterns inside normally and abnormally growing embryonic hearts would help inform the clinical progression of congenital heart defects and develop treatment strategies to restore these defects. We previously developed a system to quantify local fluid forces within growing embryonic heart where we combined imaging modalities with computational fluid dynamics (CFD), and quantified the hemodynamics within the AV canal and OFT in chicks. In the current study, we analyzed how altered hemodynamics drives changes in local gene expression and downstream morphogenesis of AV valves. Perturbed blood flow was created via either left atrial ligation (LAL) at HH24 or right atrial ligation (RAL) at HH25, to constrict blood flow on respective side of the heart. Hemodynamic environment in the AV canal for operated embryos were compared to control groups via doppler ultrasound at HH31. Gene expression levels were analyzed using RT-PCR. Heart morphology was analyzed at HH31 via micro-CT and histology. RT-PCR results at HH25 showed that LAL caused a drastic decrease in gene expression levels in LV myocardium (VEGFA expression 18.2±5.6%, BMP2 expression 21.7±1.4% compared to controls) and in AV cushions (VEGFA expression 9.8±8.1%, BMP2 expression 3.5±1.9 %), whereas in RV myocardium, expression levels were not affected significantly (VEGFA expression 77.5±5.8% , BMP2 expression 66.0±10.0%). Doppler ultrasound showed that neither peak blood velocities nor time averaged velocities in right and left AV canal are different for both LAL and RAL at HH31, suggesting WSS levels are not different between experimental groups (max shear stress 287dynes/cm2) at that stage. For LAL embryos, left AV valve area was smaller (48±4% vs. 67±6%, p<0.05, valve areas normalized to total left and right AV valve areas) and right valve area was bigger (52±4% vs. 33±6%, p<0.05) compared to controls, whereas in RAL embryos, opposite was true at HH31, right AV valve are was smaller (12±5 % vs. 33±6%, p<0.05) and left AV valve area was larger (88±5% vs %67±6, p<0.05). The ratio of right ventricle to left ventricle was significantly larger in LAL embryos compared to RAL embryos (1.1 vs 0.55). Our results show that morphological abnormalities follow the alterations in gene expression levels which are caused by changes in mechanical signals due to altered hemodynamics. We found that at later stages hemodynamics is restored to keep the blood circulation normal, with an altered morphology.

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/content/papers/10.5339/qproc.2012.heartvalve.4.1
2012-05-01
2019-08-22
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http://instance.metastore.ingenta.com/content/papers/10.5339/qproc.2012.heartvalve.4.1
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  • Accepted: 24 May 2012
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