mentioned above, the CNS blood vessels also show a very high pericyte coverage. In addition, blood vessels in the CNS are covered by astrocyte end-foot processes. The role of astrocytes in the BBB has been investigated extensively, which has led to the suggestion that astrocytes play an active role in promoting endothelial BBB formation [38]. Much less is known about whether pericytes contribute to the formation and maintenance of BBB. Brain injury is often accompanied by microvessel leakage. Dore-Duffy et al. [39] showed that pericytes migrate away from the endothelium in response to brain injury and in association with BBB disruption. Whether dissociation of pericytes from the CNS microvessel plays a causal role in BBB disruption needs further investigation. Viable pericyte-deficient mouse models will be valuable tools for such studies. It has been suggested using in vitro assays that pericyte-derived Ang1 and TGF-β induce expression of components crucial for formation of the tight junction between capillary endothelial cells [40]. TGF-β signaling is important for maintenance or formation of the BBB. In this respect, it is interesting that gap junctions between endothelial cells and pericytes appear to be needed for activation of latent TGF-β [41]. As mentioned above, peri- cyte-derived angiopoietin-1 signaling via Tie2 is thought to mediate vessel stabilization, implicating a direct role in the regulation of endothelial junctions and the BBB. Overexpression of angio- poietin-1 in mice results in partially leakage-re- sistant vessels [42].

Maintenance of the Adult Vasculature

PDGF-B mutants have made us realize that pericytes have important functions not only during development but also in adult homeostasis and pathological processes, such as tumor angiogenesis [43]. It has been observed that loss of pericytes along retinal microvessels is one of the earliest cellular changes occurring as a result of diabetes, and hence potentially constituting a key step in the pathogenesis of diabetic retinopathy [44, 45].

Indeed, several studies in mice have suggested that pericyte dropout might have a causal role in diabetic retinopathy. Endothelial-specific knockout of PDGF-B leads to severely reduced pericyte numbers along microvessels. Animals where pericyte numbers were reduced by more than 90% in the CNS compared to control animals developed retinopathy without diabetes [46]. On the other hand, diabetic animals lacking one pdgfb allele showed increased pericyte loss compared to diabetic wild-type mice, indicating that PDGF-B might be an important survival factor for pericytes during diabetic challenge [47]. Mice that express retention motif-deficient PDGF-B have abnormal pericyte coverage with pericytes partially detached from the abluminal vessel surface. Also these mice develop severe retinopathy, showing that not only presence of pericytes but also the proper association between pericytes and endothelial cells is important for vessel protection [15].

There are indications that pericytes regulate deposition of BM. Thickening of BM around blood vessels is observed in diseased conditions and in aging animals [48]. Mice expressing retention motif-deficient PDGF-B show abnormal deposition of collagen IV in the BM around aorta [31]. Age-related thickening of the BM around vessels coincides with reduced pericyte number and altered association with endothelium in rat retina [48]. Altered thickness of vessel BM is also observed in diabetes. Ultrastructural studies of skin microvessels of patients with lipoid proteinosis also indicate that pericytes contribute to excess deposition of BM [49].

Acknowledgements

We acknowledge research support from the Karolinska Institute, The Ludwig Institute for Cancer Research, The Swedish Cancer Foundation, The Inga-Britt and Arne Lundberg, Knut and Alice Wallenberg and Ragnar Söderberg Foundations and the Association for International Cancer Research (UK).

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