Role of the Heparin Binding Domain in the Clearance and Localization of Vascular Endothelial Growth Factor

AbstractPathological healing characterized by abnormal angiogenesis presents a serious burden to patients’ quality of life requiring innovative treatment strategies. Glycosaminoglycans (GAG) are important regulators of angiogenic processes. This experimental and computational study revealed how sulfated GAG derivatives (sGAG) influence the interplay of vascular endothelial growth factor (VEGF)165 and its heparin-binding domain (HBD) with the signaling receptor VEGFR-2 up to atomic detail. There was profound evidence for a HBD-GAG-HBD stacking configuration. Here, the sGAG act as a “molecular glue” leading to recognition modes in which sGAG interact with two VEGF165-HBDs. A 3D angiogenesis model demonstrated the dual regulatory role of high-sulfated derivatives on the biological activity of endothelial cells. While GAG alone promote sprouting, they downregulate VEGF165-mediated signaling and, thereby, elicit VEGF165-independent and -dependent effects. These findings provide novel insights into the modulatory potential of sGAG derivatives on angiogenic processes and point towards their prospective application in treating abnormal angiogenesis.

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Vascular Endothelial Growth Factor Heparin-Binding Domain Contributes to Proliferative Signaling and Pulmonary Functional Outcomes in Compensatory Lung Growth

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2020.07.780 ◽

2020 ◽

Vol 231 (4) ◽

pp. S215-S216

Author(s):

Lumeng J. Yu ◽

Victoria H. Ko ◽

Duy T. Dao ◽

Jordan D. Secor ◽

Bennet S. Cho ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Functional Outcomes ◽

Vascular Endothelial ◽

Heparin Binding ◽

Lung Growth ◽

Compensatory Lung Growth ◽

Heparin Binding Domain ◽

Endothelial Growth Factor ◽

Proliferative Signaling

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The heparin-binding domain confers diverse functions of VEGF-A in development and disease: a structure–function study

Biochemical Society Transactions ◽

10.1042/bst0371201 ◽

2009 ◽

Vol 37 (6) ◽

pp. 1201-1206 ◽

Cited By ~ 40

Author(s):

Dominik Krilleke ◽

Yin-Shan Eric Ng ◽

David T. Shima

Keyword(s):

Vascular Endothelial Growth Factor ◽

Binding Domain ◽

Vascular Endothelial ◽

Heparin Binding ◽

Splice Isoforms ◽

Molecular Features ◽

Neuropilin 1 ◽

Heparin Binding Domain ◽

Endothelial Growth Factor ◽

Vascular Branching

The longer splice isoforms of VEGF (vascular endothelial growth factor)-A, including VEGF164(165), contain a highly basic HBD (heparin-binding domain). This domain allows these isoforms to interact with and localize to the HS (heparan sulfate)-rich extracellular matrix, and bind to the co-receptor Nrp-1 (neuropilin-1). Heparin-binding VEGF-A isoforms are critical for survival: mice engineered to express exclusively the non-heparin-binding VEGF120 have diminished vascular branching during embryonic development and die from postnatal angiogenesis defects shortly after birth. Although it is thought that the HBD contributes to the diverse functions of VEGF-A in both physiological and pathological processes, little is known about the molecular features within this domain that enable these functions. In the present paper, we discuss the roles of the VEGF HBD in normal and disease conditions, with a particular focus on the VEGF164(165) isoform.

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