doi: 10.1161/01.CIR.0000165120.35950.C7
(Circulation. 2005;111:e297-e298.)
© 2005 American Heart Association, Inc.
Correspondence |
Letter Regarding Article by Shyu et al, "Functional Recovery of Stroke Rats Induced by Granulocyte Colony-Stimulating Factor–Stimulated Stem Cells"
Department of Cardiology, Center for Cardiovascular Research, Berlin, Germany, Department of Cardiology, Albert Ludwigs University, Freiburg, Germany
Max Planck Institute for Experimental Neurology, Cologne, Germany
Shuy and coworkers investigated the effect of granulocyte colony-stimulating factor (G-CSF) in a right cerebral artery ligation model in the rat.1 They reported that G-CSF treatment led to a significant reduction in infarct size, improved neural plasticity, and enhanced vascularization. They concluded that the latter effects are largely the result of mobilization of autologous hemopoietic stem cells into circulation, enhancing their translocation into ischemic brain, and thus significantly improving lesion repair.
The authors omitted one important physiological mechanism in the brain—the impact of the collateral circulation (arteriogenesis) on the restoration of tissue perfusion on hypoperfusion. Our recent studies into brain arteriogenesis2–4 demonstrated for the first time that similar to the cardiac and peripheral circulation, cerebrovascular occlusions are partly compensated by the growth of preexisting collateral arteries (ie, by the active remodeling of the arterial vessel wall that is characteristic of arteriogenesis). Importantly, the therapeutic application of CSFs significantly accelerated this process and led to a drastic reduction in infarct size as compared with the control group.
Indeed, Shuy and coworkers reported that they found increased numbers of stem cells in the perivascular location of the penumbra. Did the authors investigate whether these vessels are positive for proliferation markers ? It is tempting to speculate that the latter arteries are collateral vessels perfusing the area at risk (penumbra) from outside the risk region. Hence, this observation would be in agreement with ours.
It is worth mentioning that any stem cell invading an ischemic tissue will suffer from low oxygen tension because the feeding arteries are still occluded (middle cerebral artery). The angiogenic formation of new capillaries within the hypoperfused tissue will not change the perfusion level and will only marginally reduce total vascular resistance; therefore, angiogenesis is a much less efficient way to improve blood flow than is the growth of collateral arteries. In fact, as the vascular resistance of the collateral arteries declines with the fourth power of vessel diameter, an increase by only 10%, more than doubles blood conductance. These collateral pathways are, in most cases, located outside the risk region, however.
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- Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY, Yen PS, Li H. Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation. 2004; 110: 1847–1854.
[Abstract/Free Full Text]
- Schneeloch E, Mies G, Busch HJ, Buschmann IR, Hossmann KA. Granulocyte-macrophage colony-stimulating factor-induced arteriogenesis reduces energy failure in hemodynamic stroke. Proc Natl Acad Sci U S A. 2004; 101: 12730–12735.
[Abstract/Free Full Text]
- Buschmann IR, Busch HJ, Mies G, Hossmann KA. Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte-macrophage colony-stimulating factor. Circulation. 2003; 108: 610–615.
[Abstract/Free Full Text]
- Busch HJ, Buschmann IR, Mies G, Bode C, Hossmann KA. Arteriogenesis in hypoperfused rat brain. J Cereb Blood Flow Metab. 2003; 23: 621–628.[CrossRef][Medline]
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Response
Neuro-Medical Scientific Center, Tzu-Chi Buddhist General Hospital, Tzu-Chi University, Hualien, Taiwan
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan
Institute of Molecular Biology, Academia Sinica, Institute of Biochemistry, National Yang-Ming University, Taipei, Taiwan
We thank Drs Buschmann and Hossmann for their comments on our study. We are honored to have the opinions of the researchers who made such great contributions in deciphering the molecular mechanisms of "neovessel" biology.1 In our recent study of stroke rats treated with granulocyte colony-stimulating factor (G-CSF),2 we found that mobilized stem cells or endothelial progenitor cells (EPCs) labeled with BrdU contributed to "re-endothelialization and angiogenesis" in the perivascular area of the penumbric region of the brain. To further confirm this phenomenon, we conducted experiments to demonstrate that the proliferative marker ki673 was present in fluorescein isothiocyanate-dextran–perfused cerebral vessels of the penumbric region in the G-CSF–treated group (data not shown). These results suggested that mobilized EPCs contribute to "line-up" and "build" new vessels in the ischemic brain. We also found, however, that the EPCs incorporative rate for the construction of new blood vessels in the absence of brain ischemia was relatively low, which was because of the lack of upregulation of the chemoattractive power of stromal cell-derived factor-1 and its receptor CXC chemokine receptor 4. Furthermore, we conclude that the efficiency of neovascularization may not be solely attributable to the incorporation of EPCs but also may be influenced by the release of angiogenic substances, including vascular endothelial growth factor, surrounding the microenvironment of the ischemic brain.
We fully agree with Dr Buschmann and Dr Hossmann’s opinion on the remodeling of the arterial wall—that collateral circulation may restore brain tissue perfusion in the ischemic brain. Nevertheless, based on our data,2 it may be speculated that the power of both "old-fashioned" collaterals and "fancy" stem cells contributed to reconstruct the vascular network to improve the tissue perfusion. A previous study suggested, however, that the angiogenic formation of new capillaries in the penumbric region may be "nonfunctional" and does not improve the blood perfusion level of the ischemic brain.4 To optimize therapeutic neovasculization, treatment strategies should therefore focus on strengthening re-endothelialization and remodeling of collateral circulation in ischemic tissue.
In conclusion, our studies suggest that the administration of exogenous G-CSF stimulates both angiogenesis and neurogenesis in the ischemic penumbric areas. Moreover, direct neuroprotection may reduce ischemic injury in the acute phase, whereas neurogenesis, angiogenesis, or both may contribute to longer-term repair of the injured brain.
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- Zonta M, Angulo MC, Gobbo S, Rosengarten B, Hossmann KA, Pozzan T, Carmignoto G. Neuron-to-astrocyte signaling is central to the dynamic control of brain microcirculation. Nat Neurosci. 2003; 6: 43–50.[CrossRef][Medline]
[Order article via Infotrieve]
- Shyu WC, Lin SZ, Yang HI, Tzeng YS, Pang CY, Yen PS, Li H. Functional recovery of stroke rats induced by granulocyte colony-stimulating factor-stimulated stem cells. Circulation. 2004; 110: 1847–1854.
[Abstract/Free Full Text]
- Busch HJ, Buschmann IR, Mies G, Bode C, Hossmann KA. Arteriogenesis in hypoperfused rat brain. J Cereb Blood Flow Metab. 2003; 23: 621–628.[CrossRef][Medline]
[Order article via Infotrieve]
- Wang Y, Kilic E, Kilic U, Weber B, Bassetti CL, Marti HH, Hermann DM. VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena. Brain. 2005; 128: 52–63.
[Abstract/Free Full Text]
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Circulation 2005 111: 2413.[Full Text]
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