Review ArticlePericytes and vascular stability
Introduction
Angiogenesis, the process of new blood vessel formation from preexisting vessels, normally occurs as a sequential series of morphogenetic events resulting in a functional network of vessels in which the cellular and extracellular matrix components show a very low degree of turnover. The quiescent, stabilized, vasculature dominates in the healthy adult individual. Angiogenesis in adults is generally a rare event, observed only in conjunction with pregnancy, the female reproductive cycle and following prolonged and heavy physical exercise. In marked contrast, the formation of new blood vessels in pathological processes, such as tumors and chronic inflammations, does not lead to stable, quiescent and optimally functional vessels. Instead, the vessels remain in a continuous dynamic state of growth, regression and remodeling. Tumor vessels are functional in the sense that they are capable of supporting tumor growth, but they display a range of abnormalities reflecting compromised function. They are generally fragile and leaky, leading to hemorrhage and increased interstitial fluid pressure [1], [2], [3]. Inefficient blood flow caused by poor hierarchical anatomy and organization of the tumor vasculature leads to ischemia and necrosis, which are common hallmarks of rapidly growing tumors. It is hoped that these features of tumor vessels, and their lack of stability, should make them sufficiently distinct from the vessels of the normal tissues to allow selective targeting by anti-angiogenic drugs [4]. Whereas we have witnessed during the past few years the first successful and clinically meaningful results of anti-angiogenic treatment of human cancer [5], there seem to be good prospects for further improvement. Understanding the molecular and cellular mechanisms regulating vascular stability may be a key to such advancements. Some published data suggest that the most unstable vessel branches may also be those most susceptible to anti-angiogenic therapy [6]. Other data suggest that anti-angiogenic therapy may have the combined effect of reducing vessel density and promoting vessel stabilization [7], [8]. Once we have learned more about the mechanisms involved in vessel stabilization, we may find new ways to treat tumors, perhaps by destabilizing vessels and improve the effects of current anti-angiogenic drugs, Although it appears as a formidable challenge to achieve selective destabilization of tumor vessels while leaving normal vessels intact, there are reasons for optimism based on recent studies in animal models [9], [10]. Furthermore, it might prove useful to impair the process of de novo stabilization of tumor vessels, even if selective destabilization of already stabilized tumor vessels cannot be achieved.
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Pericytes and vascular stability
How are vessels stabilized? Current ideas propose the involvement of at least two components: the perivascular extracellular matrix–in particular the vascular basement membrane–and the recruitment and integration of pericytes into the vessel wall. Pericytes are vascular smooth muscle (vSMC) lineage cells that occur as solitary cells with characteristic morphology embedded in the basement membrane of microvessels [11], [12]. Through long cytoplasmic processes that extend along and encircle the
Intercellular signals between endothelial cell and pericytes as putative mediators of vascular stability
Several ligand–receptor systems have been implicated in regulating vessel maturation and stability through the interaction between endothelial cells and pericytes. Below, we discuss published data on four such pathways: transforming growth factor (TGF)-β and its receptor system, angiopoietins 1 and 2 and their receptor Tie2, platelet-derived growth factor (PDGF)-B and its receptor PDGF receptor beta (PDGFR-β), and sphingosine-1-phosphate (S1P) and its receptor S1P1. We also mention recent data
TGF-β, a cytokine with multiple roles in vessel formation and stabilization
TGF-β is a family of multifunctional cytokines with several roles in the vasculature. It regulates basic functions of endothelial cells, such as cell proliferation and differentiation, through ALK1 and ALK5 receptors and their downstream signaling pathways, involving Smad1/5 and Smad2/3, respectively [20]. TGF-β is expressed by a number of cell types, including endothelial and mural cells, and, depending on the context and concentration, it may be either pro- or anti-angiogenic. TGF-β seems to
Angiopoietins and Tie receptors regulate vascular stability
The angiopoietins, Ang1 and Ang2, regulate vessel stability by activating (Ang1) or antagonizing (Ang2) signaling via the Tie 2 receptor (Fig. 1B). Ang1 and Tie2 knockouts die at midgestation from similar cardiovascular defects, suggesting generalized problems with both angiogenesis and vessel maturation and stabilization. The vessels show poorly developed basement membrane and detachment of pericytes. Ang1 reduces vascular permeability in the skin [34], in tumors [35] and in an in vitro model
PDGF-B and PDGFR-β promote pericyte recruitment
PDGF-B and PDGFR-β play critical roles in the recruitment of pericytes to newly formed blood vessels. Knockout of pdgfb or pdgfrb in mice leads to a pronounced reduction in microvessel pericyte coverage in many, but not in all, organs [48], [49], [50], [51]. PDGF-B is expressed by endothelial cells, in particular in angiogenic sprouts and remodeling arteries, and triggers migratory and proliferative responses in PDGFR-β carrying pericytes (Fig. 1C). The importance of the endothelial source of
S1P and S1P1 in mural cell recruitment and vessel stabilization
S1P1 (Edg1) is a widely distributed G-protein-coupled receptor for sphingosine-1-phosphate (S1P). Stimulation of S1P1 triggers a Gi-linked pathway affecting proliferation, survival and migration of cells [59], [60]. Disruption of the S1P1 gene in mice causes embryonic lethality around E12–14 due to vascular defects caused by aberrant recruitment of vSMCs to the developing aorta [61]. Similar defects have been observed in endothelium-specific, but not in vSMC-specific, S1P1 ablation,
Other pathways potentially involved in endothelial/pericyte interactions
Retinoids are anti-angiogenic and lead to abnormal ratios of endothelial and mural cells in chicken chorioallantoic membrane (CAM) assays and in blood vessel generated from embryonic stem cells [65], [66]. The importance of endogenous retinoic acid (RA) during vasculogenesis was demonstrated using retinalaldehyde dehydrogenase 2 (Raldh2)-deficient mice, which cannot synthesize RA. Blood vessels in Raldh2−/− mice are dilated and composed of increased numbers of endothelial cells, but lack
Acknowledgments
We acknowledge research support from the Ludwig Institute for Cancer Research, the Karolinska Institute, the Swedish Cancer Foundation, the Inga-Britt and Arne Lundberg, Knut and Alice Wallenberg and Söderberg Foundations and the Association for International Cancer Research (UK).
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