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PII S1050-1738(01)00163-3 TCM The development of a hierarchical vas- cular network by remodeling of the pri- mary capillary plexus is known as angio- genesis. This process is essential for many physiological as well as pathologi- cal conditions, including tumor progres- sion (Folkman 1995). Several intra- and intercellular signals control the mecha- nisms that initiate the sprouting of new vessels or pruning of the pre-existing ones. Vascular endothelial growth factor (VEGF) and related growth factors are important regulators of this complex molecular phenomenon. VEGF is the most potent angiogenic inducer and is known to initiate two major steps in blood vessel formation: proliferation and migration of the endothelial cells (Conn et al. 1990, Connolly et al. 1989a, and 1989b, Dvorak et al. 1995, Ferrara 1995, Ferrara and Henzel 1989). Members of the VEGF family belong to the cysteine-knot superfamily of growth factors. These bioactive proteins display a common structural architecture (based on a cyclic-knot of cysteines) despite little homology in their amino acid se- quence. This cysteine-knot motif gives stability to the three-dimensional structure of these proteins (McDonald and Hendrickson 1993, Murray-Rust et al. 1993). It also supports the solvent- exposed, receptor-binding surface of these polypeptides and brings the key residues involved in receptor recogni- tion into spatial proximity. The VEGF family consists of six structurally related proteins: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placenta growth factor (PlGF). PlGF shares 40% amino acid sequence identity with VEGF. • PlGF: Genomic Structure and Splice Variants The human PlGF gene is located on chro- mosome 14 of the genome (Maglione et al. 1993) and consists of seven exons. PlGF-1 was first isolated from the hu- man placenta and was characterized as being highly homologous to VEGF (Mag- lione et al. 1991). This was followed by the discovery of PlGF-2, an isoform of PlGF-1. The two isoforms (PlGF-1/PlGF 131 and PlGF-2/PlGF 152 ) are generated by differential splicing of the PlGF mRNA (Maglione et al. 1993). A third isoform of the PlGF gene (Figure 1) was charac- terized recently with the use of cDNA from the human terminal placental tis- Role of Placenta Growth Factor in Cardiovascular Health Shalini Iyer and K. Ravi Acharya* Placenta growth factor (PlGF), a member of the cysteine-knot family, is an angiogenic protein. The PlGF gene has been conserved across differ- ent species of the animal kingdom. It is expressed primarily in the pla- centa, 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 mod- ulate 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. (Trends Cardiovasc Med 2002;12:128–134) © 2002, Elsevier Science Inc. Shalini Iyer and K. Ravi Acharya are at the Department of Biology and Biochemistry, Univer- sity of Bath, Claverton Down, Bath, United Kingdom. *Address correspondence to: K. Ravi Acharya, Department of Biology and Biochemistry, University of Bath, South Building, Claverton Down, Bath BA2 7AY, UK. Tel.: +44-1225- 826238; fax: +44-1225-826779; e-mail: K.R.Acharya@bath.ac.uk. © 2002, Elsevier Science Inc. All rights reserved. 1050-1738/02/$-see front matter