Therapeutic angiogenesis

Abstract

McCarthy's recent correspondence1.McCarthy M.J. Developing strategies for therapeutic angiogenesis: vascular endothelial growth factor alone may not be the answer.Br J Plast Surg. 2003; 56: 77Google Scholar elegantly articulates a new direction for angiogenesis research in which more than one agent is administered and in which temporal considerations are fundamental. With an ever-increasing understanding of the biological properties of the multitude of substances involved in new blood vessel formation, this attempt to mimic normal physiology more closely is a logical progression of the research milestones to which McCarthy refers. Vascular endothelial growth factor (VEGF) and angiopoietin-1 have received specific reference in both the aforementioned correspondence and in recent published research.2.Visconti R.P. Richardson C.D. Sato T.N. Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor.Proc Natl Acad Sci USA. 2002; 99 (Epub 2002 June 04): 8219-8224Google Scholar, 3.Thurston G. Complementary actions of VEGF and angiopoietin-1 on blood vessel growth and leakage.J Anat. 2002; 200: 575-580Google Scholar, 4.Shyu K.G. Chang H. Isner J.M. Synergistic effect of angiopoietin-1 and vascular endothelial growth factor on neoangiogenesis in hypercholesterolemic rabbit model with acute hindlimb ishaemia.Life Sci. 2003; 73: 563-579Google Scholar VEGF (A165) is the most studied and a particularly potent angiogen. Angiopoietin-1 is now recognised as an important agent in stabilising newly formed blood vessels and preventing leakage therefrom. To this list could be added innumerable substances important in the highly complex physiological process of angiogenesis. The VEGF family for example, consists of at least five members in the human (VEGF A, VEGF B, VEGF C, VEGF D, placental growth factor) each with a separate genetic locus. Splice isoforms of VEGF A and VEGF B expand the family further. In almost all published work to date the term VEGF is used to refer to the specific isoform VEGF A165. It is becoming important to use a more precise language as the different isoforms are proving to have diverse functions in the overlapping fields of angiogenesis, lymphangiogenesis and tumour growth. While VEGF A165 has been at the centre of most published research, the other splice isoforms of VEGF A, as well as the VEGF B, VEGF C, VEGF D and placental growth factor isoforms have been considered in noticeably fewer angiogenesis research studies to date. In the relative paucity of studies in which these proteins have been considered they have been shown to be of promise. There is justifiable optimism that VEGF B and VEGF D may prove of therapeutic value in the future.5.Silvestre J.S. Tamarat R. Ebrahimian T.G. LeRoux A. Clergue M. Emmanuel F. Duriez M. Schwartz B. Branellec D. Levy B.I. Vascular endothelial growth factor-B promotes in vivo angiogenesis.Circ Res. 2003; Google Scholar, 6.Rissanen T.T. Markkanen J.E. Gruchala M. Heikura T. Puranen A. Kettunen M.I. Kholova I. Kauppinen R.A. Achen M.G. Stacker S.A. Alitalo K. Yla-Herttuala S. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses.Circ Res. 2003; 92: 1098-1106Google Scholar The potential of these angiogens in combination with VEGF A and angiopoietins should not be ignored. With the intention of determining the ideal cocktail of recombinant proteins to administer to ischaemic tissue, each VEGF family member should be considered as a separate agent with a potential application which differs from its siblings.