Dose-Dependent Modulation of Choroidal Neovascularization by Plasminogen Activator... Author Response: PAI-1 and Ocular Angiogenesis

1 October 2003

Jean-Marie Rakic ,
Vincent Lambert, Jean-Michel Foidart, Agnès Noel

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Re: Author Response: PAI-1 and Ocular Angiogenesis

Email Jean-Marie Rakic, et al.

In the Letter to the Editor from Clark and Penn, the authors express a number of concerns regarding the role played by PAI-1 in ocular neovascularization and our interpretation of the clinical performance of anecortave acetate in the treatment of exudative macular degeneration.

First of all, the aim of our study was not to fully explain the clinical performance of anecortave acetate. We simply pointed out that depending on its concentration, PAI-1 could behave both as a pro- and antiangiogenic agent in a murine model of choroidal neovascularization, suggesting therefore that drugs (like anecortave acetate) interacting with that pathway might potentially give rise to paradoxical effects.¹ This seemed to be the case with anecortave treatment, in which higher doses were not active on choroidal neovascularization compared to lower doses.²

Clark and Penn suggest a discrepancy between the dual role of PAI-1 on choroidal angiogenesis that we reported earlier and their own result showing only an inhibitory effect of recombinant PAI-1 injected intravitreally in a rat model of retinopathy of prematurity.³ In our opinion, PAI-1 effects on angiogenesis can hardly be explained without assuming a bell-shaped curve. Indeed, it has been demonstrated previously in vivo in several unrelated models of angiogenesis (tumoral, choroidal, corneal) that the presence of PAI-1 was a necessary condition for angiogenesis to occur.^4-6 On the other hand, several groups reported that high doses of PAI-1 had obviously an inhibitory effect.^1,3,7,8 We should keep in mind however that in mice, physiological circulating concentrations of PAI-1 are around 2 ng/ml.⁹ In the Penn study, the inhibitory levels (with local intraocular injections) were evident with mg/ml concentrations of PAI-1.

Data giving the precise relationship between anecortave dose and local PAI-1 protein concentrations are, to our best knowledge, not known. Consequently, the mechanism of action of anecortave via PAI-1 modulation remains hypothetical and a matter of debate. We agree therefore with Clark and Penn that further investigation is certainly required to better define both alternative mechanisms of action of anecortave as well as its effects on local PAI-1 levels.

Jean-Marie Rakic^1,2
Vincent Lambert²
Jean-Michel Foidart²
Agnès Noel²

¹Department of Ophthalmology, University of Liège, Liège, Belgium
²Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium

References

1. Lambert V, Munaut C, Carmeliet P, et al. Dose-dependent modulation of choroidal neovascularization by plasminogen activator type 1: implications for clinical trials. Invest Ophthalmol Vis Sci. 2003;44:2791-2797.
2. D’Amico DJ, Goldberg MF, Hudson H, et al. Anecortave acetate as a monotherapy for the treatment of subfoveal lesions in patients with exudative age-related macular degeneration: interim (6 months) analysis of clinical safety and efficacy. Retina. 2003;23:14-23.
3. Penn JS, Rajaratnam VS. Inhibition of retinal neovascularization by intravitreal injection of human rPAI-1 in a rat model of retinopathy of prematurity. Invest Ophthalmol Vis Sci. In press.
4. Bajou K, Noel A, Gerard RD, et al. Absence of host plasminogen activator inhibitor I prevents cancer invasion and vascularization. Nat Med. 1998;4:923-928.
5. Lambert V, Munaut C, Noel A, et al. Influence of plasminogen activator inhibitor type 1 on choroidal neovascularization. FASEB J. 2001;15:1021-1027.
6. Gutierrez LS, Schulman A, Brito-Robinson T, et al. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor type 1. Cancer Res. 2000;60:5839-5847.
7. Devy L, Blacher S, Grignet-Debrus C, et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor is dose dependent. FASEB J. 2002;16:147-154.
8. McMahon GA, Petitclerc E, Stefansson S, et al. Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis. J Biol Chem. 2001;276:33964-8.
9. Carmeliet P, Moons L, Lijnen R, et al. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Circulation. 1997,96:3180-3191.