Viral Vascular Endothelial Growth Factors Vary Extensively in Amino Acid Sequence, Receptor-binding Specificities, and the Ability to Induce Vascular Permeability yet Are Uniformly Active Mitogens

Abstract

Infections of humans and ungulates by parapoxviruses result in skin lesions characterized by extensive vascular changes that have been linked to viral-encoded homologues of vascular endothelial growth factor (VEGF). VEGF acts via a family of receptors (VEGFRs) to mediate endothelial cell proliferation, vascular permeability, and angiogenesis. The VEGF genes from independent parapoxvirus isolates show an extraordinary degree of inter-strain sequence variation. We conducted functional comparisons of five representatives of the divergent viral VEGFs. These revealed that despite the sequence divergence, all were equally active mitogens, stimulating proliferation of human endothelial cells in vitro and vascularization of sheep skin in vivo with potencies equivalent to VEGF. This was achieved even though the viral VEGFs bound VEGFR-2 less avidly than did VEGF. Surprisingly the viral VEGFs varied in their ability to cross-link VEGFR-2, induce vascular permeability and bind neuropilin-1. Correlations between these three activities were detected. In addition it was possible to correlate these functional variations with certain sequence and structural motifs specific to the viral VEGFs. In contrast to the conserved ability to bind human VEGFR-2, the viral growth factors did not bind either VEGFR-1 or VEGFR-3. We propose that the extensive sequence divergence seen in the viral VEGFs was generated primarily by selection against VEGFR-1 binding.

Chimeric VEGF-E NZ7 /PlGF Promotes Angiogenesis Via VEGFR-2 Without Significant Enhancement of Vascular Permeability and Inflammation

“…Unlike VEGF-A 165 , structurally, VEGF-E has no basic stretch at the carboxy-terminal; functionally, VEGF-E does not use VEGFR-1 to transmit its downstream signaling. [12][13][14][15][16] Previous findings demonstrate that loop-1 and loop-3 structures of Orf-virus NZ7 -derived VEGF-E NZ7 are essential for VEGFR-2 binding. 17 On the other hand, neither edema nor subcutaneous hemorrhage presents in VEGF-E NZ7 transgenic (Tg) mice.…”

Structural determinants of growth factor binding and specificity by VEGF receptor 2

“…All VEGF-A isoforms bind to VEGFR-1 and VEGFR-2, whereas PlGF and VEGF-B are specific for VEGFR-1. Furthermore, pox viruses encode VEGF variants collectively called VEGF-E that specifically bind to VEGFR-2 (23)(24)(25).…”

Crystal Structures of Novel Vascular Endothelial Growth Factors (VEGF) from Snake Venoms

“…VEGF-A, which was the first VEGF to be discovered, is a homodimeric glycoprotein and is physiologically expressed as four splicing isoforms (comprising 121, 165, 189, and 206 residues). To date, several VEGF-A-related proteins have been identified in mammals and viruses, thus forming the VEGF gene family, which consists of five mammalian groups (VEGF-A, VEGF-B, VEGF-C, VEGF-D, and the placental growth factor; PlGF) and a Parapoxvirus-encoded group (viral VEGF; also denoted as VEGF-E) (2)(3)(4). Similarly to the VEGF ligands, four VEGF receptors have been identified.…”