Endothelial cells by inactivation of VHL gene direct angiogenesis, not vasculogenesis via Twist1 accumulation associated with hemangioblastoma neovascularization

Ying Wang; Dan-Qi Chen; Ming-Yu Chen; Kai-Yuan Ji; De-Xuan Ma; Liang-Fu Zhou

doi:10.1038/s41598-017-05833-9

Endothelial cells by inactivation of VHL gene direct angiogenesis, not vasculogenesis via Twist1 accumulation associated with hemangioblastoma neovascularization

Sci Rep. 2017 Jul 14;7(1):5463. doi: 10.1038/s41598-017-05833-9.

Authors

Ying Wang¹, Dan-Qi Chen¹, Ming-Yu Chen¹, Kai-Yuan Ji¹, De-Xuan Ma², Liang-Fu Zhou³

Affiliations

¹ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China.
² Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China. madexuan03@126.com.
³ Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, 200040, China. lfzhouc@126.com.

Abstract

Inactivation of the VHL tumour suppressor gene is a highly frequent genetic event in the carcinogenesis of central nervous system-(CNS) hemangioblastomas (HBs). The patterning of the similar embryonic vasculogenesis is an increasing concern in HB-neovascularization, and the classic vascular endothelial growth factor (VEGF)-mediated angiogenesis driven by VHL loss-of-function from human endothelium have been questioned. With this regard, we identify a distinct, VHL silencing-driven mechanism in which human vascular endothelial cells by means of increasing cell proliferation and decreasing cell apoptosis, is concomitant with facilitating accumulation of Twist1 protein in vascular endothelial cells in vitro. Importantly, this molecular mechanism is also pinpointed in CNS-HBs, and associated with the process of HB-neovascularization. In contrast with recent studies of HB-neovascularization, these modified cells did not endow with the typical features of vasculogenesis, indicating that this is a common angiogenesis implementing the formation of the vascular network. Taken together, these findings suggest that vasculogenesis and angiogenesis may constitute complementary mechanisms for HB-neovascularization, and could provide a rational recognition of single anti-angiogenic intervention including targeting to the Twist1 signalling for HBs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Apoptosis
Cell Cycle / genetics
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms / blood supply
Cerebellar Neoplasms / genetics*
Cerebellar Neoplasms / metabolism
Cerebellar Neoplasms / pathology
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Gene Ontology
HEK293 Cells
Hemangioblastoma / blood supply
Hemangioblastoma / genetics*
Hemangioblastoma / metabolism
Hemangioblastoma / pathology
Human Umbilical Vein Endothelial Cells / cytology
Human Umbilical Vein Endothelial Cells / metabolism
Humans
Male
Middle Aged
Molecular Sequence Annotation
Neovascularization, Pathologic / genetics*
Neovascularization, Pathologic / metabolism
Neovascularization, Pathologic / pathology
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / genetics
Protein Isoforms / metabolism
RNA, Small Interfering / genetics
RNA, Small Interfering / metabolism
Signal Transduction
Twist-Related Protein 1 / genetics*
Twist-Related Protein 1 / metabolism
Von Hippel-Lindau Tumor Suppressor Protein / antagonists & inhibitors
Von Hippel-Lindau Tumor Suppressor Protein / genetics*
Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

Nuclear Proteins
Protein Isoforms
RNA, Small Interfering
TWIST1 protein, human
Twist-Related Protein 1
Von Hippel-Lindau Tumor Suppressor Protein
VHL protein, human