Depolymerized hyaluronan induces vascular endothelial growth factor, a negative regulator of developmental epithelial-to-mesenchymal transformation

Laurel S. Rodgers, Sofia Lalani, Katharine M. Hardy, Xueyu Xiang, Derrick Broka, Parker B Antin, Todd D Camenisch

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Cardiac malformations constitute the most common birth defects, of which heart septal and valve defects are the most frequent forms diagnosed in infancy. These cardiac structures arise from the endocardial cushions through dynamic interactions between cells and the extracellular matrix (cardiac jelly). Targeted deletion of the hyaluronan synthase-2 (Has2) gene in mice results in an absence of hyaluronan (HA), cardiac jelly, and endocardial cushions, a loss of vascular integrity, and death at embryonic day 9.5. Despite the requirements for Has2 and its product, HA, in the developing heart, little is known about the normal processing and removal of HA during development. Cell culture studies show that HA obtains new bioactivity after depolymerization into small oligosaccharides. We previously showed reduction in Has2 expression and diminished presence of HA at later stages of heart development as tissue remodeling formed the leaflets of the cardiac valves. Here we show that small oligosaccharide forms of HA (o-HA) act antagonistically to developmental epithelial-to-mesenchymal transformation (EMT), which is required to generate the progenitor cells that populate the endocardial cushions. We further show that o-HA induces vascular endothelial growth factor (VEGF), which acts as a negative regulator of EMT. This is the first report illustrating a functional link between oligosaccharide HA and VEGF. Collectively, our data indicate that following endocardial cell EMT, native HA is likely processed to o-HA, which stimulates VEGF activity to attenuate cardiac developmental EMT.

Original languageEnglish (US)
Pages (from-to)583-589
Number of pages7
JournalCirculation Research
Volume99
Issue number6
DOIs
StatePublished - Sep 2006

Fingerprint

Epithelial-Mesenchymal Transition
Hyaluronic Acid
Vascular Endothelial Growth Factor A
Endocardial Cushions
Oligosaccharides
Heart Valves
Heart Septal Defects
Cell Communication
Extracellular Matrix
Blood Vessels
Stem Cells
Cell Culture Techniques

Keywords

  • Endocardial cushion
  • Epithelial-to-mesenchymal transformation
  • Hyaluronan
  • VEGF

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Depolymerized hyaluronan induces vascular endothelial growth factor, a negative regulator of developmental epithelial-to-mesenchymal transformation. / Rodgers, Laurel S.; Lalani, Sofia; Hardy, Katharine M.; Xiang, Xueyu; Broka, Derrick; Antin, Parker B; Camenisch, Todd D.

In: Circulation Research, Vol. 99, No. 6, 09.2006, p. 583-589.

Research output: Contribution to journalArticle

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