The Role of VEGF in the Extremities
Vascular endothelial growth factor (VEGF) is a pro-angiogenic cytokine that has a strong stimulatory effect on endothelial cell proliferation and migration. The use of VEGF in treating vascular conditions affecting the extremities, such as peripheral arte
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The Role of VEGF in the Extremities Brendan A.S. McIntyre, Takayuki Asahara, and Cantas Alev
Abstract Vascular endothelial growth factor (VEGF) is a pro-angiogenic cytokine that has a strong stimulatory effect on endothelial cell proliferation and migration. The use of VEGF in treating vascular conditions affecting the extremities, such as peripheral artery disease (PAD) and critical limb ischemia (CLI), has been studied in both basic research and clinical settings for over 30 years. In this chapter, we will discuss the animal models and applied treatments that have been attempted in this arena, with an emphasis on clinical translation. Novel combined treatments pairing cellular therapy with VEGF gene therapy will also be discussed. Keywords VEGF • VEGF165 • VEGF121 • Ischemia • Peripheral artery disease • Critical limb ischemia
8.1 VEGF in Therapeutic Angiogenesis and VEGF Isoforms Vascular endothelial growth factor (VEGF) was originally discovered more than 30 years ago and has been one of the most extensively studied cytokines known to the field of biomedicine [1]. VEGF is an angiogenic factor that has been associated with enhanced endothelial cell migration, proliferation, and vessel repair [2, 3]. The VEGF family of genes is comprised of five members, VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PGF or placental growth factor, with signaling occurring through one of three receptors, VEGFR1 (FLT-1), VEGFR2 (FLK-1/KDR) or
B.A.S. McIntyre Miltenyi Biotec Inc., 2303 Lindbergh St, Auburn, CA, USA T. Asahara Tokai University School of Medicine, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan C. Alev (*) Kyoto University, Center for iPS Cell Research and Application (CiRA), 53 Kawahara-cho, Shogoin, Sakyo-ku, 606-8507 Kyoto, Japan e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2017 Y. Higashi, T. Murohara (eds.), Therapeutic Angiogenesis, DOI 10.1007/978-981-10-2744-4_8
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VEGFR3 (FLT-4), and co-receptor neuropilin-1 (NRP1). Interestingly, two additional VEGF-A homologues not expressed in humans have been found to occur outside of the traditional VEGF family, known as VEGF-E and VEGF-F. VEGF-E occurs as a single exon-less cDNA found in the genomes of Orf viruses [4], and VEGF-F refers to venom-type VEGFs found in a number of venomous snake species [5]; both VEGF-E and VEGF-F preferentially bind to VEGFR2 and cause edema and vessel leakiness. In the field of biomedicine, the VEGF family member most commonly associated with clinical intervention due to its strong pro-angiogenic activity in both normal development and pathological settings is VEGF-A [3]. Despite the existence of at least seven reported isoforms, there are four major isoforms of VEGF-A, VEGF-121, VEGF-165, VEGF-189, and VEGF-206, which are produced via alternative splicing and differ by the presence or absence of sequences in exons 6 and 7 [6]. VEGF-165 and VEGF-121 are the only VEGF isoforms to have been used in a clinical setting to treat CLI to date and will be the focus of this chapter. Of th
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