Pericytes, an overlooked player in vascular pathobiology

Abstract

Pericytes are a heterogeneous population of cells located in the blood vessel wall. They were first identified in the 19th century by Rouget, however their biological role and potential for drug targeting have taken time to be recognised. Isolation of pericytes from several different tissues has allowed a better phenotypic and functional characterization. These findings revealed a tissue-specific, multi-functional group of cells with multilineage potential. Given this emerging evidence, pericytes have acquired specific roles in pathobiological events in vascular diseases. In this review article, we will provide a compelling overview of the main diseases in which pericytes are involved, from well-established mechanisms to the latest findings. Pericyte involvement in diabetes and cancer will be discussed extensively. In the last part of the article we will review therapeutic approaches for these diseases in light of the recently acquired knowledge. To unravel pericyte-related vascular pathobiological events is pivotal not only for more tailored treatments of disease but also to establish pericytes as a therapeutic tool.

Keywords: Cancer stem cells; Diabetic nephropathy; Diabetic retinopathy; Pericyte fibrosis; Pericytes; Perivascular stem cells.

Fig. 1

Progression of diabetic non-proliferative retinopathy. Progression of early-stage non-proliferative retinopathy to proliferative retinopathy. Elevated glucose levels will cause apoptotic cell death of pericytes. This will lead to a more permeable blood vessels and subsequent endothelial cells which will increase leakiness of vessels even more. Loss of pericytes and endothelial will increase fluid leakage in the retina as well as immune cell infiltration. These intra-ocular vascular changes will then contribute to the development of proliferative retinopathy.

Fig. 2

Interaction between pericytes and other vascular players in tumour. In normal condition ECs are stabilised by surrounding pericytes. In tumour this balanced is altered. A) In tumoural angiogenesis, pericytes could be recruited on site and stabilise the new formed vasculature via VEGF secretion. This can contribute to nourish the cancer cells, favouring tumour growth. Cancer cells can contribute to this process directly localizing in perivascular position. CSCs have the ability to differentiate in functional pericytes. B) Tumoural angiogenesis is highly disorganised, morphological changes do not allow cell-to-cell contact either between EC themselves or ECs and pericytes. The increase in vascular permeability facilitate the intravasion of cancer cells into the bloodstream. Hypoxia is a key condition for EMT to happen, promoting cancer cell mobilization. C) Drug resistance to anti-angiogenesis treatment can be due to pericytes. Therapy targeting ECs leave pericytes alive, forming a frame to be repopulated by ECs. Even in a combined strategy versus ECs and pericytes, CSCs in perivascular position can continue to act as pericytes.