Brief review
Role of Placenta Growth Factor in Cardiovascular Health☆

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Abstract

Placenta growth factor (PlGF), a member of the cysteine-knot family, is an angiogenic protein. The PlGF gene has been conserved across different species of the animal kingdom. It is expressed primarily in the placenta, especially in the later stages of gestation. PlGF expression is upregulated during pathological conditions such as ischemia of the heart and myocardial infarction. It is now known that PlGF can modulate the activity of vascular endothelial growth factor, the most potent of all angiogenic inducers and hence makes it an attractive target for therapeutic strategies. Recent structural studies on different isoforms of PlGF promise to reveal important topological and molecular details of these proteins that may be of potential use in the design of effective small molecule inhibitors to combat pathological angiogenesis.

Section snippets

PlGF: Genomic Structure and Splice Variants

The human PlGF gene is located on chromosome 14 of the genome (Maglione et al. 1993) and consists of seven exons. PlGF-1 was first isolated from the human placenta and was characterized as being highly homologous to VEGF (Maglione et al. 1991). This was followed by the discovery of PlGF-2, an isoform of PlGF-1. The two isoforms (PlGF-1/PlGF131 and PlGF-2/PlGF152) are generated by differential splicing of the PlGF mRNA (Maglione et al. 1993). A third isoform of the PlGF gene (Figure 1) was

PlGF: Molecular Characterization

PlGFs are biologically active as homodimers. PlGF-1 has a molecular mass of ∼46 kDa (dimer) and is composed of 131 amino acid residues per monomer. It has been shown that PlGF-1 is a secretory protein and undergoes N-glycosylation. PlGF-2 consists of 170 amino acid residues prior to signal peptide (18 amino acid residues in length) cleavage. Compared to PlGF-1, PlGF-2 that is associated with the membrane has a highly cationic 21 amino acid insert at the carboxy-terminal of the protein (Cao et

PlGF: Receptors and Their Expression

The distinct patho-physiological roles of the PlGF isoforms are mediated by binding to the fms-like tyrosine kinase receptor-1 (Flt-1/VEGFR-1; Figure 2; Park et al. 1994). It has been shown that PlGF-1 binds to Flt-1 with high affinity, transphosphorylates Flt-1, and thus activates the signal transduction cascade. PlGF-1 does not induce autophosphorylation of kinase-insert domain receptor (KDR/VEGFR-2; Cao et al. 1996, Landgren et al. 1998, Sawano et al. 1996, Terman et al. 1994). VEGF, on the

PlGF: Protein Structure

The three-dimensional crystal structure of recombinant human PlGF-1 was recently elucidated at 2.0 Å resolution (Iyer et al. 2001; Figure 3). More recently, the resolution was extended to 1.55 Å (Iyer et al., unpublished results). Here we shall review the functional implications of PlGF-1 corresponding to the structural details at this higher resolution.

PlGF-1 structure is remarkably similar to VEGF-A121 (Figure 3). It occurs as a biological homodimer in which the monomers initially associate

PlGF: Structure and Drug Design

Structure-based drug design of small molecule antagonists or agonists requires a detailed three-dimensional structural and functional characterization of the target molecule. The structure of PlGF-1 shows that although it has a structural fold very similar to that of VEGF, it displays important conformational differences, especially in the flexible loops that form part of the receptor-binding region of PlGF-1. It has been known that the solvent-exposed loops undergo concerted movements, which

Role of PlGF-1 and Its Receptors in Angiogenesis

Initial experiments on PlGF-1 were rife with contradictions. There were two main schools of thought: one considered PlGF-1 to be angiogenic and the other opposed this view. Although in vitro and in vivo experiments by Ziche et al. (1997) showed that PlGF-1 induces formation of blood vessels and is chemotactic as well as mitogenic on certain types of endothelial cells (postcapillary venule ECs), these results were questioned for a long time. It is now generally believed that PlGF does play an

PlGF and Cardiovascular Diseases

The frontiers of cardiovascular health have expanded ever since scientists, worldwide, have taken an interest in the therapeutic use of VEGF in cardiovascular diseases (Zachary et al. 2000). VEGF is the angiogenic cytokine that has been shown experimentally to be responsible for initiation of angiogenesis. It is believed that VEGF is a promising candidate in therapeutic angiogenesis because of its ability to induce vasodilation and enhance vascular permeability. Therapeutic angiogenesis, as

Future Prospects

Conformational differences at the receptor-binding interface between the structures of PlGF-1 and VEGF-A121, despite a high degree of sequence homology, have uncovered crucial structural insights that are valuable in the rational design of novel angiogenesis inhibitors. Further structural studies on PlGF-1 are required, studies that are largely based on receptor-ligand complexes. The structural basis behind Flt-1 receptor specificity of PlGF-1 and the other isoforms may lead to the development

Conclusion

Researchers have spent the last three decades trying to bring the totality of the complex phenomenon of blood vessel formation into perspective. Three-dimensional structures of the various proteins involved in angiogenesis have given the researchers great headway into realizing this goal and simultaneously in the design of small molecule inhibitors to fight diseases related to angiogenesis. The recent work by Carmeliet et al. (2001) has introduced a new thought process. The structure of PlGF-1,

Acknowledgements

We thank our colleagues in the Structural Biology Group for critical reading of the manuscript. Our research on PlGF is supported by the Medical Research Council, UK, through a Programme Grant (G9540039) to K.R.A. S.I. is supported through a post-graduate studentship and an ORS award from the University of Bath. K.R.A. wishes to acknowledge the award of a Royal Society-Leverhulme Trust (UK) Senior Research Fellowship.

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