doi: 10.1161/01.ATV.0000236220.06886.e3
© 2006 American Heart Association, Inc.
Editorials |
Arteries or Veins?
VEGF Helps EPCs Choose Their cAMP
From Inserm U689, Centre de Recherche Cardiovasculaire Lariboisière, Paris, France.
Correspondence to Ziad Mallat, Inserm U689, Centre de Recherche Cardiovasculaire Lariboisière, 41 Bd de la Chapelle, 75010 Paris, France. E-mail mallat{at}larib.inserm.fr
Blood vessels are initially formed by a process termed vasculogenesis, which denotes the in situ differentiation of vascular progenitor cells into endothelial cells and their organization into primary vessels.1 As vessels begin a remodeling process, they undergo localized proliferation and regression, as well as programmed branching and migration. One of the first events that takes place with the onset of circulation is the specification of arteries versus veins.
See page 1977
Until recently, arterial versus venous fate was known as a late event in the vascular development process, resulting from hemodynamic flow differences between the two types of vessels.2 However, specific markers for arteries and veins were discovered, which labeled endothelial cells from early developmental stages onwards, before the assembly of any vascular wall. For the arterial system, ephrinB2, neuropilin 1, and members of the Notch pathway appear to play critical roles.2 Other molecules such as EphB4 or neuropilin-2 are specifically expressed in the venous system. The expression of these markers is segregated to the future arterial and venous parts of the primitive vascular network despite the absence of flow, suggesting that arterial and venous fate is established in early progenitors. The notch signaling pathway has been implicated as a prime player in arterial versus venous switch. Administration of a dominant-negative form of Suppressor of Hairless (the major downstream effector of Notch signaling) resulted in decreased expression of arterial markers, whereas expression of an activated notch construct induced ectopic arterial markers in the vein system.3,4 This arterial–venous decision is guided, at least in part, by the Notch target gridlock. Graded attenuation of gridlock expression, by mutation or morpholino antisense, increases the expression of the venous marker EphB4 receptor while reducing the expression of the arterial marker ephrin-B2, and leads to a progressive ablation of arterial regions while expanding contiguous regions of the vein.3 Nevertheless, changes in flow modulate gene expression and cell fate,5 suggesting that arterial versus venous fate is likely controlled by both hemodynamic flow patterns and genetic programming. However, the molecular and cellular pathways involved in arterial versus venous cell fate decision remain to be fully defined.
In previous works, Yurugi-Kobayashi et al have developed embryonic stem cell–derived VEGFR2 cell differentiation system. Interestingly, this system allows the dissection of the cellular and molecular mechanisms of endothelial differentiation and specification.6 In the present study,7 the authors took advantage of their embryonic stem cell differentiation assay to assess the specific role of adrenomedullin/cAMP pathway in activation and differentiation of arterial endothelial cells from vascular progenitors. They showed that addition of cAMP or adrenomedullin enhanced VEGF-induced endothelial cell differentiation. The arterializing effect of VEGF and adrenomedullin/cAMP pathway was blunted by inhibition of Notch signaling. Interestingly, iloprost, an analogue of prostaglandin (PG) I2 that elevates intracellular cAMP, showed no arterial inducing effects, suggesting that other counter-regulatory pathways were induced by iloprost and that adrenomedullin/cAMP pathway is a specific inducer of arterial endothelial cells from vascular progenitor cells. This is consistent with the abnormal arterial vascular phenotype associated with targeted null mutation of the adrenomedullin gene.8,9 Unexpectedly, Notch overexpression alone did not induce arterial differentiation, suggesting that Notch signal is not sufficient to mediate arterial endothelial cell induction. Obviously, additional works are required to define the precise molecular interactions among adrenomedullin, cAMP, and Notch pathways.
The results of the present study might also have implications for stem cell therapy. Despite the excitement regarding the possible clinical use of progenitor cells, recent studies have shown that age and other risk factors for cardiovascular diseases reduce the availability of vascular progenitor cells and impair their function to varying degrees. For example, patients with coronary artery disease showed reduced levels and functional impairment of EPCs, which correlated with risk factors for coronary artery disease.10 It is therefore tempting to speculate that combining progenitor cell implantation with complementary proangiogenic therapy might overcome these deficiencies. In support of this view, the addition of VEGF2 to EPC cultures results in significant and dose-dependent decrease in EPC apoptosis.11 Four weeks after myocardial infarction, animals treated with combination therapy showed improved fractional shortening, increased capillary density, and reduced infarct size compared with cell therapy alone or VEGF2 gene therapy alone. Combination therapy was also associated with an increased number of circulating EPCs, 1 week after myocardial infarction.11 In the present study, the authors clearly showed that adrenomedullin/cAMP pathway increased survival of VEGFR2+ progenitor cells. Adrenomedullin also increases angiogenic potency of bone marrow cell transplantation,12 enhances proliferation and migration of cultured endothelial cells, and promotes angiogenesis.13 All together, these results suggest that activation of adrenomedullin/cAMP pathway or Notch signaling may overcome therapeutic failures of stem cell administration (eg, reduction in progenitor cells survival or adhesion) and may also offer safety advantages by allowing lower dosing strategies.
In conclusion, this interesting study provides a potent novel system to dissect progenitor cell differentiation and may contribute to the development of efficient cell-based therapies.
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Disclosures
None.
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Related Article:
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Arterioscler. Thromb. Vasc. Biol. 2006 26: 1977-1984.[Abstract] [Full Text] [PDF]
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