There are several pieces of evidence that suggest that neovascularization differs depending on its location within the body and the underlying disease process. EG-VEGF and BV8 stimulate angiogenesis in some tissues and not others. They may be unique or there may be other tissue-specific stimulators of angiogenesis that have not yet been identified. Their existence indicates that the "formula" for angiogenesis may have different " ingredients" in different tissues. The norrin/Fz4 ligand-receptor pair controls organ-specific vascularization in the retina and inner ear, which suggests that a signaling system used throughout the body may have a structurally unrelated ligand in one or two tissues that use the system for a specific purpose - perhaps adding to local diversity in regulation of the vasculature. HIF-1 is a central player, because it upregulates several proangiogenic proteins, but it does not upregulate the same ones in all cells; therefore, it may have somewhat different effects in different tissues. Id proteins are transcription factors that downregulate the antiangiogenic TSP1 and the proangiogenic receptor CXCR4. Their effect on angiogenesis in a particular tissue or disease process varies depending on which of these two opposite effects predominates. The local environment influences gene expression in endothelial cells. Endothelial cells participating in neovascularization express proteins that are not expressed in endothelial cells of normal vessels, forming the basis for vascular targeting. Even normal vascular cells in different tissues express different proteins, which has led to the concept of "molecular ZIP codes." Differences in gene expression underlie differences in cell response to various signaling molecules and are likely to contribute to different responses to proangiogenic and antiangiogenic molecules in different vascular beds. There are many examples of vascular cells in different tissues, or sometimes in the same tissue, that respond to the same stimulus in different ways. In some cases, the mechanism is known or suspected, and in other cases it is not. 1. Cells can be programmed to respond to the same angiogenic stimulus in different ways. This programming is exemplified by tip and stalk cells, specialized endothelial cells that occur in close proximity and respond to VEGF in different ways. 2. A receptor expressed in different cells may act differently. For example, in vascular endothelial cells, Ang2 blocks phosphorylation of Tie2; but when Tie2 is expressed in other cell types, Ang2 promotes phosphorylation of Tie2 rather than blocking it. It is not known whether such differences also exist among different types of endothelial cells. 3. Increased expression of VEGF can stimulate sprouting of new vessels from some vascular beds, but not others. Permissive factors are needed for VEGF to induce sprouting, and in some vascular beds they are constitutively expressed. 4. Increased expression of Ang1 promotes neovascularization in skin and suppresses it in the retina and choroid. The mechanism causing this difference is not known. 5. Increased expression of TIMP1 blocks neovascularization in some tissues, but stimulates it in the retina. A possible explanation for the different effects of proteinases or proteinase inhibitors in different settings is that proteolytic cleavage of ECM or ECM-associated proteins can yield both stimulators and inhibitors of angiogenesis, and one or the other may predominate, depending on the specific makeup of the ECM in a tissue. 6. Cell types that are unique to a certain tissue, such as the RPE, may influence new vessel growth or regression, adding to local differences. The tissue-specific aspects of angiogenesis have several important implications. It should not be assumed that experiments in chick chorioallantoic membrane, the cornea, or tumor models predict what will happen with regard to retinal and choroidal neovascularization. Normal retinal vascular development is, at best, an imperfect model of retinal neovascularization in adults. Although these processes have some similarities, they also have many differences, and effects of drugs or gene products on retinal vascular development may not predict effects on retinal neovascularization. Likewise, just because one VEGF antagonist inhibits retinal vascular development and another one does not, it does not follow that the latter one is safer in adults. In several respects, mature retinal vessels in adults do not behave like newly developed retinal vessels in neonates. The potential for developmental stage-specific effects on ocular vessels should not be overlooked. Increased expression of VEGF in RPE cells during embryonic life results in thickening of the choroid due to increased developmental growth, but if VEGF is expressed in the RPE in adult animals, there is no phenotype. It appears that embryonic choroidal vessels are responsive to VEGF, but adult choroidal vessels are not. This is similar to the developmental window between P0 and P7 when the superficial capillaries of the retina are responsive to VEGF. Also, although increased expression of VEGF does not cause sprouting of new vessels from adult choriocapillaris, it does not mean that that VEGF does not provide survival signals to the choriocapillaris in adults. VEGF is essential for the maintenance of fenestrated capillaries in several organs, and since the choriocapillaris is fenestrated, the effects of long-term VEGF blockade should be studied. Caution should be exercised in designing clinical trials to investigate a drug for retinal or choroidal neovascularization based on clinical or preclinical results in other vascular beds. For example, based on the effects of interferon α2a in patients with cutaneous hemagiomas and results in a monkey model in which interferon α2a inhibited iris neovascularization,115 it was hypothesized that interferon α2a would also inhibit choroidal neovascularization. However in a large trial, patients with neovascular AMD treated with interferon α2a did worse than patients treated with placebo.116 Although it is important to identify differences among different types of neovascularization, it is equally important to identify similarities. The central role of VEGF as a stimulator and survival signal in most types of neovascularization makes it a major therapeutic target. VEGF antagonists have been found to provide benefit for tumor angiogenesis and choroidal neovascularization, and several new VEGF antagonists are being tested for each indication. Another VEGF family member, P1GF, has been implicated as a stimulator of both tumor and ocular angiogenesis, and two other family members, VEGF-C and -D, function primarily as stimulators of lymphangiogenesis, but they can also stimulate angiogenesis. Thus, it is reasonable to attempt to neutralize all members of the VEGF family in the treatment of retinal and choroidal neovascularization. VEGF antagonists are not likely to be displaced in the treatment of choroidal neovascularization, but rather will serve as the foundation to which other drugs are added. Likely candidates are antagonists of Tie2, PDGF-B, and integrins, to eliminate survival signals for new vessels and, we hope, allow for regression. Because HIF-1 upregulates several angiogenic factors, it is also an appealing target, because antagonizing it should resemble combination treatment. Finally, unlike many organs, the eye affords good opportunities for local, sustained delivery. In addition to identifying molecular targets and developing good antagonists, a critical challenge for the future is to determine pharmacokinetics with different modes of administration and to optimize delivery.
ASJC Scopus subject areas