LONDON The therapeutic potential of being able to control the growth of blood vessels is enormous. Switching off blood vessel growth could help defeat malignant tumors, which need to form new blood vessels once they reach a certain size if they are to obtain enough nutrients and oxygen. Turning on blood vessel growth could make it possible to overcome the lack of oxygen suffered by an area of heart muscle following a myocardial infarction, or help heal wounds such as diabetic ulcers.
These are the broad aims of a group of researchers in Finland, which has been painstakingly adding to what is known about the molecular basis for the control of angiogenesis, the growth of new blood vessels. The substances involved are called vascular endothelial growth factors (VEGFs), and their receptors (VEGFRs).
Last year, Kari Alitalo, research professor at the Finnish Academy of Sciences, and colleagues at the University of Helsinki and Harvard Medical School, in Boston, reported that a member of the family of VEGFs, called VEGF-C, causes enlargement and proliferation of the endothelial cells lining the lymphatic vessels. The report appeared in the May 30, 1997, issue of Science. (See BioWorld International, June 4, 1997, p. 1.)
Now, Alitalo, together with colleagues at the Haartman Institute at the University of Helsinki, and Daniel Dumont, of the University of Toronto, have investigated the role of the receptor to which VEGF-C binds, which is called VEGFR-3. VEGFR-3 is normally expressed in the developing blood vessels of mouse embryos from embryonic day eight onward, but in adult mice this receptor is normally expressed only in the lymphatic vessels.
Alitalo¿s group generated mice which lacked a functional gene for VEGFR-3. Heterozygous mice and embryos appeared to be normal, but no live-born animals which were homozygous for the deleted gene resulted.
The researchers therefore examined embryos at various stages of gestation, as they report in their paper in the Oct. 30 issue of Science, titled: ¿Cardiovascular failure in mouse embryos deficient in VEGF receptor-3.¿
Commercial Development Delayed
Alitalo told BioWorld International: ¿In the early mouse embryo, the vascular system resembles a network of vessels, rather like a fisherman¿s net. Later on in gestation, this network is remodeled into a tree-like hierarchy of big vessels and smaller branches. What we found was that this remodeling process was absent in the homozygous embryos, none of which developed after 10.5 days¿ gestation.¿ Some large vessels did form, but these were abnormally organized and had defective lumens. Fluid accumulated in the pericardial cavity, followed by cardiovascular failure.
This finding was ¿somewhat unexpected,¿ Alitalo said, because of the team¿s earlier findings that VEGFR-3 tends to be restricted to the lymphatic vessels in adult animals, and that it induces growth of the lymphatic vessels in adults.
¿This paper tells us,¿ Alitalo added, ¿that the function of this receptor in the embryo is in the development of the cardiovascular system and blood vessels, and this is before the lymphatic vessels have developed. Later, in adult animals, the function shifts to the lymphatic system. In addition, during the past year, we have also found that the embryonic pattern of expression of this receptor can be reacquired when resting vessels start to grow again. It seems that this receptor can be up-regulated in some processes where blood vessels grow. So we presume that, in these conditions, the growth factor that binds to this receptor can also play a role in blood vessel formation and this is a striking area for applications.¿
The Finnish researchers have been supported by the Finnish Academy of Sciences and the State Technology Development Centre. To protect the intellectual property rights of the team¿s findings, the university has set up a company called Helsinki University Licensing Ltd., which is in partnership with the London-based Ludwig Institute for Cancer Research, which has a network of 10 research centers worldwide.
Discussions with biotechnology companies over the development of VEGF-C have been taking place, but at a recent meeting in Sweden, the researchers and representatives of the Ludwig Institute decided to delay any decision on commercial involvement for another six months. Professor Munro Neville, associate director of the Ludwig Institute for Cancer Research, said: ¿We decided that more science needed to be done so that we could ascertain more fully the clinical potential [of these substances].¿
Work on applying the findings in the clinic is continuing. Alitalo is collaborating with Seppo Yld-Herttuala at the University of Kyopio, in Finland, on preclinical studies in larger laboratory animals using VEGF-C to stimulate the formation of collateral vessels around a narrowed vessel in the heart. This could lead to a drug able to treat the ischemia of heart muscle which can follow a myocardial infarction, or ischemia of the lower limbs.
Another line of research is to find out whether VEGF-C can promote healing of the endothelium following treatment to widen the lumen of a blood vessel. In this procedure, called balloon angioplasty, a balloon is inflated inside the vessel to clear a blockage or narrowing. In up to a third of patients, however, the narrowing of the vessel recurs because inflating the balloon damages the lining of the blood vessel, allowing platelets to adhere and stimulate the smooth muscle cells in the vessel wall to proliferate. Being able to heal the damage rapidly could prevent subsequent narrowing.
Imaging Of Lymph System Studied
Patients with breast cancer, who frequently suffer a condition called lymphoedema if they have surgery to remove lymph nodes from the armpit on the affected side, may also benefit from treatment with VEGF-C, if this could stimulate the regrowth of lymphatic vessels.
Studies are also under way to exploit VEGFR-3 in imaging of the lymphatic system, and Alitalo predicts that antibodies that bind both to VEGF-C and to VEGFR-3 will provide useful tools for scientific research. ¿We are very certain that VEGF-C will make it to the clinics in the conditions mentioned here,¿ he concluded. ¿It looks very promising indeed.¿