doi: 10.1161/ATVBAHA.0000265524.41376.e7
© 2007 American Heart Association, Inc.
Editorials |
Choking off Plaque Neovascularity
A Promising Atheroprotective Strategy or A Double-Edged Sword?
From the Division of Cardiology and Atherosclerosis Research Center, Department of Medicine and the Burns and Allen Research Institute, Cedars-Sinai Medical Center and the David Geffen School of Medicine at UCLA, Los Angeles, Calif.
Correspondence to Prediman K. Shah, MD, Division of Cardiology, Cedars Sinai Medical Center, Suite 5531, 8700 Beverly Blvd., Los Angeles, CA 90048. E-mail Shahp{at}cshs.org
"For every complex problem there is a simple solution—and it’s wrong."— H.L. Mencken
Atherosclerosis is a highly prevalent disease that results from a complex interplay between lipids, endothelial cells, immunoinflammatory cells, cytokines, extracellular matrix, and neovascularization.1 Several lines of evidence suggest that increased adventitial and plaque neovascularity, commonly observed in murine and human atherosclerosis, plays an important role in progression and, possibly, destabilization of atherosclerosis.1–9 Increased plaque neovascularity may contribute to plaque progression by its link to inflammation, as a source of intraplaque hemorrhage and plaque lipid (Figure).1,5,7–9
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See page 1095
The precise mechanisms contributing to increased plaque neovascularity remain to be defined; however, inflammation and one or more angiogenic growth factors have been implicated. One of the pathways for angiogenesis leading to neovascularization involves the family of vascular endothelial growth factor(s) (VEGF) and their receptors (VEGFR). Therefore, VEGF and VEGFR mediated angiogenesis has emerged as a potential target for modulation of atherosclerosis.3,6 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Petrovan et al report on a novel approach to inhibiting plaque angiogenesis in hypercholesterolemic mice. The authors used a previously reported oral plasmid DNA vaccine expressing VEGF receptor 2 (VEGFR2, KDR in humans/Flk-1 in mice) to test the effects of immune response against Flk-1 on angiogenesis and atherosclerosis in LDL receptor deficient mice. The effect of such a vaccine in reducing tumor angiogenesis and inhibiting growth of new or established tumors has been previously demonstrated.10 This vaccine appears to work by activating a cytotoxic CD8+ T-cell response against Flk-1 expressing activated endothelial cells because depletion of CD8+, but not CD4+ T-cells, was previously shown to abrogates the anti-tumor effect of this vaccine in vivo.10 In the current manuscript, the authors report that such an oral DNA vaccine against Flk-1 suppresses angiogenesis and specific T-cell response in vitro and reduces intraplaque neovascularity and atherosclerosis in hypercholesterolemic LDL receptor deficient mice without changes in circulating lipid profile. These findings are consistent with other experimental observations that support the hypothesis that plaque angiogenesis/neovascularization and VEGF-mediated signaling pathway plays a role in murine atherogenesis and that inhibition of angiogenesis reduces atherosclerosis.2–6
This study provides interesting data regarding a novel immunomodulating strategy against atherosclerosis but also raises important additional questions that will need to be addressed. First, the magnitude of effect on lesions size, although statistically significant, is relatively modest with considerable overlap between vaccinated and control animals. The authors do not provide data to explain whether the considerable variability in the effect on lesion size is related to the extent of inhibition of plaque neovascularity or some other variables such as variations in the efficacy of expression of the DNA vaccine. Second, despite reduction in plaque size and contrary to expectation, the plaque phenotype, as reflected by the extent of plaque inflammation and plaque collagen content, was not altered. Although the precise implications of this finding are not clear, it raises potential concern that major determinants of plaque stability were not favorably affected. Third, this DNA-based vaccine appears to induce breakdown in immune-tolerance against Flk-1, an endogenous protein. In addition to endothelial cells, Flk-1 is also expressed by a variety of other cells types such as hematopoietic cells, neuronal cells, or osteoblasts (albeit with lower expression levels compared with endothelial cells) and is important in fetal development.11 Therefore it is conceivable that the cytotoxic effects elicited by this vaccine against Flk-1 bearing cells could affect normal tissue growth, remodeling, repair, or healing. In fact delayed wound healing from this vaccine has been previously reported.10 Furthermore, recent studies have shown that Flk-1 positive multipotential cardiovascular progenitor cells develop into cardiomyocyte, endothelial, and vascular smooth muscle cells12 and that vessel wall contains angiohematopoietic mesodermal stem cells with Flk-1 markers.13 At this time, the consequences of the vaccine induced activation of a cytotoxic response against these Flk-1– bearing cells remains unclear and would require further investigation. Fourth, because both vascular smooth muscle cells and endothelial cells lining the plaque express Flk-1,14,15 vaccination induced cytotoxic effects on these cells types, both of which are believed to be important contributors to plaque stability, has the potential to create more unstable lesion phenotype. Fifth, the current study reported the inhibitory effects of oral Flk-1 vaccine on progression of atherosclerosis when vaccination was initiated at 8 to 10 weeks of age before any significant lesions develop in this model; the effect on preestablished atherosclerosis were not evaluated. This is potentially important when one considers the implications of this study for humans because vast majority of patients that are considered for treatment already have established atherosclerosis. Sixth, the authors have not unequivocally proven that activation of a CD8+ mediated cytotoxic response against Flk-1 bearing endothelial cells mediates the atheroprotective effects because appropriate adoptive transfer experiments were not performed nor was the role of any humoral immune response evaluated. Finally, a word of caution: because angiogenesis contributes to formation of collateral circulation in ischemic tissues to protect against vasoocclusive events in the heart and possibly other organs such as the brain, one must exercise caution about a nonselective antiangiogenic strategy for atherosclerosis management (with the potential to inhibit collateral formation) to avoid "robbing Peter to pay Paul" effect. Recent reports of a significant increase in the risk of stroke with intraocular antiangiogenic therapy for macular degeneration16 should be a sobering reminder that such an intervention has the potential to be the proverbial "double-edged sword".
Atherosclerosis is a complex chronic immunoinflammatory disease where many components of both the innate as well as adaptive immune response have been shown to modulate the disease process.17 Selective activation of atheroprotective immunity has been shown in experimental models using immunization with antigens such as oxidized or MDA-modified LDL and apoB 100–related peptide epitopes.18–24 Limitations notwithstanding, the study by Petrovan et al provides yet another intriguing target and immunomodulating strategy thereby broadening our understanding of the pathophysiology of murine atherosclerosis and paving the way for potentially new therapeutic avenues that deserve further investigation.
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Acknowledgments |
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Disclosures
Dr Shah is a co-invator of apoB 100 related peptide vaccines and has assigned his rights to Cedars Sinai Medical Center.
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References |
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