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signaling augments LPS responses. It also 6. Jin, F.-Y., Nathan, C.F. & Ding, A. Paradoxical preser- ithelial cells, Nod2 can confer LPS respon- vation of a lipopolysaccharide response in C3H/HeJmacrophages: induction of matrix metalloproteinase- 9. J. Immunol. 162, 3596–3600 (1999).
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oup http://medicine
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The well-tempered vessel
Although gene therapy studies of angiogenesis have focused on the ability of endothelial cells to form new structures, it
has recently become clear that the subsequent stages of remodeling are crucial to attaining stable and functional
vessels. A precise balance of cell types and molecules is required for normal vessel maturation and must be considered in
the design of therapeutic angiogenic strategies.
2001 Nature Pub

the factor themselves as well as secreting metalloproteinases that release extracellu- vessels, is one of the most promising tar- lar matrix-bound VEGF (ref. 6). The recruit- gets for gene therapy. This strategy might ment of pericytes by platlet-derived growth benefit must come from double-blind, ran- lial cells is critical to the stabilization and maturation of nascent vascular structures7.
Vessels that are associated with pericytes sion are attractive, given that animal stud- often fatal. To induce angiogenesis, inves- ies show that delivery of ‘too much of a those lacking pericytes regress following tigators have delivered vascular endothe- good thing’ (such as VEGF) is deleteri- ous3–5. Although early studies focused on fibroblast growth factor (bFGF/FGF2) as re- endothelial cells and the possibility of in- breakage of vessels at sites where pericytes are absent9. In addition, in vascular beds delivery has not been highly successful in subsequent stages of remodeling and stabi- devoid of pericytes, endothelial-cell prolif- clinical trials and the most promising re- lization are crucial to attaining stable and eration appears to be unabated and exces- sults to date have been obtained via gene functional vessels. Accordingly, attention sive9. This is similar to the pathogenesis of therapy. This approach enlists cells of the to the necessary balance of both cell types and molecules in vessel maturation is im- leads to an increase in VEGF and the for- proteins using the genetic code of the de- pacting the design of novel therapeutic an- livered DNA. For example, direct intramy- Tight orchestration of the relative abun- ness7. Moreover, tumors often overexpress encoding VEGF165 or adenoviral delivery of supply, but the vessels produced have few artery disease have both yielded signifi- cells/pericytes is critical to the develop- and dysfunctional pericytes and are leaky clinical results are encouraging, in that VEGF, also alter VEGF levels by producing tumor as a ‘wound that never heals’. It is NATURE MEDICINE • VOLUME 7 • NUMBER 5 • MAY 2001
2001 Nature Publishing Group http://medicine.nature.com
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ing methods that have greater resolution.
Although VEGF can induce mature vesselsat an appropriate dosage and appears tohave a relatively wide therapeutic win- dow1,2, the balance between clinical bene- fit and toxicity is likely to differ withgenetic predisposition, age and disease Transient - V
artery disease differ significantly in their tions and this response correlates with the collateral vessels14. Regulatable vectors would facilitate modulation of VEGFdosage and, in conjunction with non-in- vasive imaging technologies (positronemission tomography and magnetic reso- nance imaging), would allow in vivo mon-itoring of the angiogenic response and the = PDGF-BB
ability to tailor therapy to the individual A1 = ANG-1
patient’s needs. Ideally, gene products oup http://medicine
A2 = ANG-2
would be synthesized under the control of = Leakage sites
a non-toxic agent that could be adminis-tered orally, providing the ability to fine- Gene therapy approaches that take into account the complex interplay of molecules and cell types tune expression levels. Several promising lishing Gr
essential for normal angiogenesis and the development of mature vessels. The left side of the figure demonstrates that too much VEGF (V) leads to formation of torturous, leaky blood vessels, typical of tu- mors. The right side of the figure demonstrates three possible therapeutic solutions to this problem. a,
VEGF alone can either be delivered over the long-term, at the appropriate dose and time using regulatable
vectors (REG-V), or transiently (transient-V) at low levels. b, VEGF can be co-delivered with genes encoding
their in vivo utility is currently limited.
proteins such as Ang-1 (A1), which stabilizes endothelium, or PDGF-BB (P), which recruits pericytes (purple cells) . c, HIF-1α is a pleiotropic transcription factor that activates endothelial cells to produce a number of
understanding of the multiple factors and factors involved in the physiologic response to hypoxia, such as VEGF, Ang-2 (A2) and PDGF-BB. A secreted 2001 Nature Pub
their roles in feedback loops and cascades peptide (PR39) increases HIF-1α half-life by inhibiting its ubiquitination.
will enhance gene therapy approaches toangiogenesis. New targets might derivefrom gene discovery efforts in other tissues therefore apparent that not only endothe- lial cells, but also other cell types such as processes similar to those involved in an- pericytes must be considered as targets for gies have emerged that address the requi- also of the plethora of implicated signal- VEGF itself is a neurotrophic factor.
Vessels differ in the molecules they express sels that retained the physiological abil- should take tissue differences into account response to inflammatory stimuli (J.
genes for investigation. Given that recent (ref. 11). A potential alternative strategy as complex as expected, functional assays plicated in pericyte recruitment, such as of genes will need to include untranslated together, these results indicate that HIF- 1α may act pleiotropically to activate an plex and, irrespective of the genes deliv- ered or the strategy employed, attention to factor-1α (HIF-1α), which increases ex- and cells—as in Bach’s Das Wohltemperierte Klavier—will be critical to ensure the long- among others10. There are currently three of regulatable vectors that operate indefi- term production of fully functional ‘well- nitely in vivo as well as non-invasive imag- NATURE MEDICINE • VOLUME 7 • NUMBER 5 • MAY 2001
2001 Nature Publishing Group http://medicine.nature.com
N E W S & V I E W S
1. Vale, P.R. et al. Left ventricular electromechanical 6. Bergers, G. et al. Matrix metalloproteinase-9 triggers Circulation 102, 2255–2261 (2000).
mapping to assess efficacy of phVEGF(165) gene the angiogenic switch during carcinogenesis. Nature 13. Li, J. et al. PR39, a peptide regulator of angiogenesis.
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cDNA to individuals with clinically significant severe Keshet, E. Selective ablation of immature blood ves- 15. Yancopoulos, G.D., Klagsbrun, M. & Folkman, J.
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& Blau, H.M. VEGF gene delivery to muscle: potential 9. Lindahl, P., Johansson, B.R., Leveen, P. & Betsholtz, C.
16. Ruoslahti, E. & Rajotte, D. An address system in the role for vasculogenesis in adults. Mol. Cell. 2, 549–558
Pericyte loss and microaneurysm formation in PDGF- vasculature of normal tissues and tumors. Annu. Rev. B-deficient mice. Science 277, 242–245 (1997).
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Department of Molecular Pharmacology tramyocardial injection of DNA expressing vascular Stanford University School of Medicine endothelial growth factor (VEGF) in a myocardial in- 12. Vincent, K.A. et al. Angiogenesis is induced in a rabbit farction model in the rat—angiogenesis and angioma model of hindlimb ischemia by naked DNA encoding formation. J. Am. Coll. Cardiol. 35, 1323–1330 (2000).
an HIF-1α/VP16 hybrid transcription factor.
Inhaled CO: Deadly gas or novel therapeutic?
CO is a poisonous gas, but under the right conditions it may serve as a novel inhalation therapy able to reduce the
oup http://medicine
consequences of acute lung injury (pages 598-604).
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nism of this surprising beneficial effect? the images of air pollution1,2, of cigarette tion of fibrin plays a pivotal role in the smoke or of suicides by inhalation of car pathophysiology of the lung injury caused exhaust fumes in closed garages. A recent by ischemia/reperfusion. The authors pro- report from the Center for Disease Control structure, regulation or tissue distribution.
pose that the beneficial effects of CO in- halation are due to a reduced deposition of fibrin in the microvasculature. Inhalation 2001 Nature Pub
(CO) poisonings on Lake Powell in Arizona of CO attenuated the deposition of fibrin and Utah3. Recently nitric oxide (NO) has Fujita et al.4 observed that in wild-type tant generated by lightning and the burn- mice, ischemia/reperfusion of the lung re- lung. Inhalation of CO also suppressed the sults in a 7–8-fold increase in the expres- gen activator inhibitor-1 (PAI-1) in lung. PAI-1 is a protein that inhibits the activ- Ignarro & Murad, Nobel Prize, 1998).
fusion, only 12% of these animals died. In ity of tissue-type plasminogen activator (t- Therefore, many of us may not be entirely contrast, HO-1–deficient mice that were PA) and by doing so reduces fibrinolysis.
surprised to learn that in this issue, Fujita et al.4 report that CO can paradoxically rescue was lethal to 50% of PAI-1–deficient mice, 1–deficient mice were given CO by inhala- whereas all wild-type mice subjected to this can function as a physiological regulator as mortality associated with ischemia/reper- croscopy analysis revealed that PAI-1 is pri- well as a toxic gas dates back to January phagocytes, which are located in lungs sub- conclude that CO does not always act as a Like CO, nitric oxide (NO) is a colorless, reports indicated that the brain, which is could serve as a novel inhalation therapy water-soluble gas. NO diffuses to adjacent normally not exposed to large quantities of cells, activates soluble guanylate cyclase heme, has an impressive ability to metabo- lize this protein. This led to the suggestion that the biological function of heme oxy- guanine monophosphate (cGMP) (Fig. 1).
other organs or tissues against oxidative Activation of sGC results in a reduction in the removal of heme, is not limited to its stress8,9, Fujita et al.4 provide evidence that the protection against injury after induc- which in turn mediates many (but not all) have been identified, including HO-1 (also tion of HO-1 is at least partly due to an en- of the effects of NO including vasodilata- known as heat shock protein 32), which is tion and inhibition of platelet adhesion.
indeed reduce the lung injury caused by is- gas (65 p.p.m.) also reduces the mortality NATURE MEDICINE • VOLUME 7 • NUMBER 5 • MAY 2001

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