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Title: Roles in vascular endotheial growth factor isoforms in the progression of infantile haemangioma
Author: Ye, Xi
ISNI:       0000 0004 5922 6012
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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Vascular endothelial growth factor A (VEGF-A) has been implicated in the pathogenesis of infantile haemangioma (I H). Despite the relatively high frequency of IH occurrence, the molecular mechanisms underlying the disease's progression and spontaneous involution are unknown and the roles of VEGF-A for this condition has been poorly described. VEGF-A can be alternative spliced into two families of isoforms, the proangiogenic VEGF-Axxxa and the anti-angiogenic VEGF-Axxxb. The aim of this study is to determine whether an increase in VEGF-Axxxb is associated with IH involution and if so, how this may be regulated and what are the effects on cell proliferation and angiogenesis. The study identified that an increase in the relative proportion of VEGFAxxxb is closely associated with IH involution and that it may be regulated by stem cell differentiation into an endothelial lineage. VEGF-A165b, the most researched on isoform of the VEGF-Axxxb family, inhibits proliferation of IH stem cells and endothelial cells as well as inhibiting the angiogenic potential of the endothelial cells via differential regulations of VEGF receptor 2 (VEGFR2) activation and degradation. Delta like ligand 4 (DLL4) has been widely associated with angiogenic sprouting both in developmental and in pathological angiogenesis, wherein a high DLL4 expression is associated with angiogenic tip cell establishment. Like VEGFR2, DLL4 levels are also differentially regulated by the VEGF-A isoforms in the endothelial cells. Furthermore,the study provide evidence that IH pericytes also express DLL4, but regulated in a VEGFR2 independent manner, may be able to cooperate with VEGF-A165b to promote blood vessel stabilisation in IH. In conclusion, increase in VEGF-A165b is closely associated with IH progression by inhibiting proliferation and angiogenesis, providing evidence VEGF-A splicing as a mechanism of IH involution. j3-receptor blockade by propranolol is an effective treatment for IH. However, it is unknown how propranolol accelerates IH involution. Literatures suggest that propranolol may target cell proliferation, angiogenesis and vasoconstriction of blood vessels in IH. This study showed that propranolol does not inhibit proliferation of IH stem cells, endothelial cells or pericytes at physiologically relevant concentrations. However, ~-receptor activation upregulates both Oct4 and Klf4, two key transcription factors involved in stem cell multipotency. In HemSCs, propranolol inhibits the upregulation of Oct4 and Klf4 by β-receptor activation. Thus, this suggests a novel mechanism by which propranolol may target IH to induce involution.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available