Neurol Sci DOI 10.1007/s10072-014-1680-1
LETTER TO THE EDITOR
Role of endothelial progenitor cells in cerebral aneurysm pathogenesis Dale Ding
Received: 29 January 2014 / Accepted: 11 February 2014 Ó Springer-Verlag Italia 2014
Dear Editor, The recently published article in Neurological Sciences by Liang et al. titled ‘Decreased levels and function of circulating endothelial progenitor cells in unruptured intracranial saccular aneurysm patients’ was very interesting [1]. The authors measured the serum levels of endothelial progenitor cells (EPC) in 24 patients with unruptured cerebral aneurysms (CA) and in 24 healthy volunteer controls. The circulating levels of EPCs were found to be significantly lower in the CA cohort than in the control cohort. Additionally, the proliferative, migratory, and adhesive capacities of EPCs in the CA cohort were significantly diminished compared to the control cohort. The results of the current study suggest that EPC dysfunction may contribute to CA formation. However, there is a lack of mechanistic data defining the molecular pathways by which EPC function is abrogated in patients with unruptured CAs. Additionally, it remains unclear if EPC dysfunction is causative of CA formation or whether it is an epiphenomenon resulting from the pathophysiological changes of the cerebral vasculature as a result of CA development. However, it would be interesting to see if either systemic (via an intravenous route) or local (via an endovascular route) administration of properly functioning EPCs results in stabilization or regression of CAs in an in vivo animal CA model. Hoh et al. [2] demonstrated expression of the chemokine stromal cell-derived factor-1 (SDF-1), also known as CXCL12, in human CAs and in elastase-induced murine
D. Ding (&) Department of Neurosurgery, University of Virginia, P.O. Box 800212, Charlottesville, VA 22908, USA e-mail: [email protected]
carotid aneurysms. In comparison, control superficial temporal arteries from the human subjects and control normal murine carotid arteries did not express SDF-1. The same study found SDF-1 to promote endothelial and inflammatory cell migration as well as endothelial cell proliferation and tube formation. Mice with elastaseinduced aneurysms were found to have increased circulating progenitor cells expressing CXCR4, the receptor for SDF-1, although the study did not specifically identify a cell subpopulation as EPCs. Blockade of SDF-1 using an anti-SDF-1 monoclonal antibody inhibited cellular proliferation in the aneurysm walls and reduced aneurysm formation in the elastase-based murine model. Maddaluno et al. [3] found endothelial-to-mesenchymal transition (EndMT) to contribute to the pathogenesis of cerebral cavernous malformations (CCM). Specifically, activation of the transforming growth factor-b (TGF-b) and bone morphogenetic protein (BMP) signaling pathways by BMP6 was implicated as the molecular driving force underlying EndMT. It is currently unknown if EndMT is involved in CA pathogenesis. Inflammation is known to play a central role in CA pathogenesis, resulting in upregulation of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), on endothelial cells [4]. This process facilitates the recruitment of inflammatory cells, such as lymphocytes and monocytes, which localize to the site of vascular injury and further propagate the inflammatory cascade. Vascular smooth muscle cells (SMC) residing in tunica media beneath the endothelium undergo phenotypic modulation in response to vascular injury and inflammation. While this process has been suggested to contribute to CA pathogenesis, the molecular mechanisms which regulate SMC phenotypic modulation within CAs have yet to be defined
123
Neurol Sci
[5]. Just as the contribution of SMC phenotypic modulation to CA pathogenesis cannot be studied without rigorous in vivo SMC lineage-tracing systems, the role of EPCs in CA formation, progression, and rupture cannot be properly defined without methods to determine their origin and fate beyond the use of cell surface markers. The present study is provoking, but further studies are necessary to elucidate the mechanisms by which EPC number and function are reduced in CA patients, and to explore potential therapeutic approaches for stabilizing or regressing CAs utilizing EPCs.
References 1. Liang C, Feng H, Deng BQ, Li ZF, Huang QH, Zhao W, Zhao WY, Yang PF, Xu Y, Zhao R, Liu JM (2014) Decreased levels and
123
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3.
4.
5.
function of circulating endothelial progenitor cells in unruptured intracranial saccular aneurysm patients. Neurol Sci 35(1):23–28. doi:10.1007/s10072-013-1459-9 Hoh BL, Hosaka K, Downes DP, Nowicki KW, Wilmer EN, Velat GJ, Scott EW (2014) Stromal cell-derived factor-1 promoted angiogenesis and inflammatory cell infiltration in aneurysm walls. J Neurosurg 120(1):73–86. doi:10.3171/2013.9.JNS122074 Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G, TournierLasserve E, Chapon F, Richichi C, Retta SF, Lampugnani MG, Dejana E (2013) EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498(7455):492–496. doi:10.1038/nature12207 Starke RM, Raper DM, Ding D, Chalouhi N, Owens GK, Hasan DM, Medel R, Dumont AS (2013) Tumor necrosis factor-alpha modulates cerebral aneurysm formation and rupture. Transl Stroke Res. doi:10.1007/s12975-013-0287-9 Starke RM, Chalouhi N, Ding D, Raper DM, McKisic MS, Owens GK, Hasan DM, Medel R, Dumont AS (2013) Vascular smooth muscle cells in cerebral aneurysm pathogenesis. Transl Stroke Res. doi:10.1007/s12975-013-0290-1
LETTER TO THE EDITOR
Role of endothelial progenitor cells in cerebral aneurysm pathogenesis Dale Ding
Received: 29 January 2014 / Accepted: 11 February 2014 Ó Springer-Verlag Italia 2014
Dear Editor, The recently published article in Neurological Sciences by Liang et al. titled ‘Decreased levels and function of circulating endothelial progenitor cells in unruptured intracranial saccular aneurysm patients’ was very interesting [1]. The authors measured the serum levels of endothelial progenitor cells (EPC) in 24 patients with unruptured cerebral aneurysms (CA) and in 24 healthy volunteer controls. The circulating levels of EPCs were found to be significantly lower in the CA cohort than in the control cohort. Additionally, the proliferative, migratory, and adhesive capacities of EPCs in the CA cohort were significantly diminished compared to the control cohort. The results of the current study suggest that EPC dysfunction may contribute to CA formation. However, there is a lack of mechanistic data defining the molecular pathways by which EPC function is abrogated in patients with unruptured CAs. Additionally, it remains unclear if EPC dysfunction is causative of CA formation or whether it is an epiphenomenon resulting from the pathophysiological changes of the cerebral vasculature as a result of CA development. However, it would be interesting to see if either systemic (via an intravenous route) or local (via an endovascular route) administration of properly functioning EPCs results in stabilization or regression of CAs in an in vivo animal CA model. Hoh et al. [2] demonstrated expression of the chemokine stromal cell-derived factor-1 (SDF-1), also known as CXCL12, in human CAs and in elastase-induced murine
D. Ding (&) Department of Neurosurgery, University of Virginia, P.O. Box 800212, Charlottesville, VA 22908, USA e-mail: [email protected]
carotid aneurysms. In comparison, control superficial temporal arteries from the human subjects and control normal murine carotid arteries did not express SDF-1. The same study found SDF-1 to promote endothelial and inflammatory cell migration as well as endothelial cell proliferation and tube formation. Mice with elastaseinduced aneurysms were found to have increased circulating progenitor cells expressing CXCR4, the receptor for SDF-1, although the study did not specifically identify a cell subpopulation as EPCs. Blockade of SDF-1 using an anti-SDF-1 monoclonal antibody inhibited cellular proliferation in the aneurysm walls and reduced aneurysm formation in the elastase-based murine model. Maddaluno et al. [3] found endothelial-to-mesenchymal transition (EndMT) to contribute to the pathogenesis of cerebral cavernous malformations (CCM). Specifically, activation of the transforming growth factor-b (TGF-b) and bone morphogenetic protein (BMP) signaling pathways by BMP6 was implicated as the molecular driving force underlying EndMT. It is currently unknown if EndMT is involved in CA pathogenesis. Inflammation is known to play a central role in CA pathogenesis, resulting in upregulation of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), on endothelial cells [4]. This process facilitates the recruitment of inflammatory cells, such as lymphocytes and monocytes, which localize to the site of vascular injury and further propagate the inflammatory cascade. Vascular smooth muscle cells (SMC) residing in tunica media beneath the endothelium undergo phenotypic modulation in response to vascular injury and inflammation. While this process has been suggested to contribute to CA pathogenesis, the molecular mechanisms which regulate SMC phenotypic modulation within CAs have yet to be defined
123
Neurol Sci
[5]. Just as the contribution of SMC phenotypic modulation to CA pathogenesis cannot be studied without rigorous in vivo SMC lineage-tracing systems, the role of EPCs in CA formation, progression, and rupture cannot be properly defined without methods to determine their origin and fate beyond the use of cell surface markers. The present study is provoking, but further studies are necessary to elucidate the mechanisms by which EPC number and function are reduced in CA patients, and to explore potential therapeutic approaches for stabilizing or regressing CAs utilizing EPCs.
References 1. Liang C, Feng H, Deng BQ, Li ZF, Huang QH, Zhao W, Zhao WY, Yang PF, Xu Y, Zhao R, Liu JM (2014) Decreased levels and
123
2.
3.
4.
5.
function of circulating endothelial progenitor cells in unruptured intracranial saccular aneurysm patients. Neurol Sci 35(1):23–28. doi:10.1007/s10072-013-1459-9 Hoh BL, Hosaka K, Downes DP, Nowicki KW, Wilmer EN, Velat GJ, Scott EW (2014) Stromal cell-derived factor-1 promoted angiogenesis and inflammatory cell infiltration in aneurysm walls. J Neurosurg 120(1):73–86. doi:10.3171/2013.9.JNS122074 Maddaluno L, Rudini N, Cuttano R, Bravi L, Giampietro C, Corada M, Ferrarini L, Orsenigo F, Papa E, Boulday G, TournierLasserve E, Chapon F, Richichi C, Retta SF, Lampugnani MG, Dejana E (2013) EndMT contributes to the onset and progression of cerebral cavernous malformations. Nature 498(7455):492–496. doi:10.1038/nature12207 Starke RM, Raper DM, Ding D, Chalouhi N, Owens GK, Hasan DM, Medel R, Dumont AS (2013) Tumor necrosis factor-alpha modulates cerebral aneurysm formation and rupture. Transl Stroke Res. doi:10.1007/s12975-013-0287-9 Starke RM, Chalouhi N, Ding D, Raper DM, McKisic MS, Owens GK, Hasan DM, Medel R, Dumont AS (2013) Vascular smooth muscle cells in cerebral aneurysm pathogenesis. Transl Stroke Res. doi:10.1007/s12975-013-0290-1
