Type-2 pericytes participate in normal and tumoral angiogenesis

Abstract

Tissue growth and function depend on vascularization, and vascular insufficiency or excess exacerbates many human diseases. Identification of the biological processes involved in angiogenesis will dictate strategies to modulate reduced or excessive vessel formation. We examine the essential role of pericytes. Their heterogeneous morphology, distribution, origins, and physiology have been described. Using double-transgenic Nestin-GFP/NG2-DsRed mice, we identified two pericyte subsets. We found that Nestin-GFP(-)/NG2-DsRed(+) (type-1) and Nestin-GFP(+)/NG2-DsRed(+) (type-2) pericytes attach to the walls of small and large blood vessels in vivo; in vitro, type-2, but not type-1, pericytes spark endothelial cells to form new vessels. Matrigel assay showed that only type-2 pericytes participate in normal angiogenesis. Moreover, when cancer cells were transplanted into Nestin-GFP/NG2-DsRed mice, type-1 pericytes did not penetrate the tumor, while type-2 pericytes were recruited during its angiogenesis. As inhibition of angiogenesis is a promising strategy in cancer therapy, type-2 pericytes may provide a cellular target susceptible to signaling and pharmacological manipulation in treating malignancy. This work also reports the potential of type-2 pericytes to improve blood perfusion in ischemic hindlimbs, indicating their potential for treating ischemic illnesses.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…Promisingly, injection of adventitial cells sorted from the human saphenous vein improved blood flow recovery following mouse hind limb ischemia and led to the formation of a denser network of capillaries and arterioles as compared to vehicle controls, suggesting the presence of a proangiogenic environment (Campagnolo et al, 2010). In addition, type 2 (nestin+/NG2+), but not type 1 (nestin-/NG2+) pericytes facilitated partial recovery following hind limb ischemia, and were found to form part of the new vessel wall (Birbrair et al, 2014b). Furthermore, Matrigel implantation of human endothelial and pericyte co-culture results in neo-formation of the microvasculature, with perfusion and anastomoses with murine blood vessels (Dar et al, 2012).…”

“…While both subpopulations are present in vessel vasculature, Birbrair et al showed that only Type 2 pericytes induce ECs to form new blood vessels in vivo and participate in tumour angiogenesis in vivo (Birbrair et al, 2014b). Ultimately, the damaged environment determines the distinction process as to whether multipotent pericytes become vascular smooth muscle cells, differentiate into progenitors or undergo both processes.…”

“…Indeed there are concerns regarding targeting pericytes in cancer treatment, as pericyte depletion triggers HGF/Met activation, a key promoter for EMT and metastasis, and is often a poor prognosis in disease progression. Again, further understanding of the subpopulations of pericytes might be beneficial, for example by only targeting Type 2 pericytes which have been shown to contribute to angiogenesis in tumour models (Birbrair et al, 2014b). In other studies targeting pericyte-EC connections, Jain et al used an anti-angiogenic therapy to destabilise pericyte-EC socket junctions by targeting ECs using tyrosine kinase inhibitors to block PDGF receptor function and enhance the inhibition of VEGF (Jain and Booth, 2003).…”

Corticosteroids and Anti-Complement Therapy in Retinal Diseases

“…Migrating endothelial cells proliferate in the surrounding extracellular matrix towards the angiogenic stimulus using integrins and other adhesion molecules. Periendothelial cells and pericytes are then recruited to promote vessel maturity (Birbrair et al 2014). …”

Evaluation of the Modulatory Effects of Copper Salts on the Process of Angiogenesis (Neovascularization) with Therapeutic Perspectives

“…T he term 'angiogenesis' refers to formation and development of new blood vessels (neovascularization) from the pre-existing ones (Birbrair et al, 2014;. It is a multi-step and complex physiological process, essential for development (Yoo and Kwon, 2013), growth (Van Lessen et al, 2015) and wound healing ( Johnson and Traci, 2014).…”