Trends in Biochemical Sciences
VEGF-receptor signal transduction
Section snippets
The VEGFs
VEGF-A, the original VEGF, exists in four different isoforms (comprising 121, 165, 189 and 206 amino acids in humans), which are generated by alternative splicing of a single pre-mRNA species. The region encoding VEGF-A spans ∼14 kb and contains eight exons (Fig. 1). The isoforms differ in their ability to bind to heparan sulfate and extracellular matrix (ECM). VEGF-A121, which lacks the region encoded by exons six and seven, does not bind to heparan sulfate and is freely diffusible, whereas
Expression, signal transduction and function of VEGFR-1
VEGFR-1 (also known as Flt-1) is a 180-kDa high-affinity receptor for VEGF-A, VEGF-B and PlGF. It is expressed in vascular endothelial cells and a range of non-endothelial cells including haematopoietic stem cells, macrophages and monocytes (Fig. 2). Vegfr-1−/− mouse embryos die at day 8.5–9 due to obstruction of vessels by an overgrowth of endothelial cells [11]. The increase in the number of endothelial progenitors in the absence of VEGFR-1 [12] implies a negative regulatory role for the
Expression, signal transduction and function of VEGFR-2
VEGFR-2 (also known as KDR or Flk-1), is a 200–230-kDa high-affinity receptor for VEGF-A, the processed forms of VEGF-C and -D, and VEGF-E. It is expressed in both vascular endothelial and lymphatic endothelial cells; its expression has also been demonstrated in several other cell types such as megakaryocytes and haematopoietic stem cells [30]. Vegfr-2−/− embryos die by embryonic day 8.5–9.5, exhibiting defects in the development of endothelial and haematopoietic precursors, indicating that the
Expression, signal transduction and function of VEGFR-3
VEGFR-3 (also known as Flt-4) is a 195-kDa high-affinity receptor for VEGF-C and VEGF-D. Distinct features of VEGFR-3 includes cleavage during synthesis within the fifth extracellular immunoglobulin loop; the two regulating polypeptides are kept together by a disulfide bridge [55]. There are two VEGFR-3 splice variants in humans, one short and one long; the latter has a C-terminal extension of 65 amino acids 56, 57 that is created by a retroviral insertion [58]. Mouse embryos lacking expression
Concluding remarks and future perspectives
There has been an intense focus in the past few years on the development of therapies based on modulation of VEGFR function. Gene therapy using VEGF-A to enhance vascularization has been tested in conditions such as cardiovascular diseases and peripheral ischaemia. However, these diseases build up over many decades and the relatively short duration of VEGF expression (e.g. upon adenovirus-mediated delivery) is likely to lead to alleviation of these conditions only temporarily. Moreover,
Acknowledgements
The authors are supported by grants from the Swedish Cancer foundation, the Association for International Cancer Research and the Novo Nordisk Foundation.
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