Pericytes, the Mural Cells of the Microvascular System

Abstract

Endothelial cells and pericytes regulate blood vessel formation, maturation and specification, all of which requires the orchestration of tightly regulated molecules. Communication between these two distinct vascular cell types occurs by direct cell contact and by paracrine signaling pathways. Pericytes and endotheslial cells are interdependent and defects in either can affect the vascular system. Loss of pericytes can lead to hyperdilated and hemorrhagic blood vessels, which lead to conditions such as edema, diabetic retinopathy, and even embryonic lethality. In tumors, although pericytes are less abundant and more loosely attached, pericyte dysfunction can result in increased endothelial cell apoptosis and metastatic spread, providing evidence that tumor pericytes are implicated in vessel maintenance, endothelial cell survival and potentially tumor dormancy. Based on their functional importance, pericytes present a complimentary target to endothelial cells in tumors. Therefore, combinatorial targeting of both cell types might have the potential to more efficiently diminish tumor vessels and halt subsequent tumor growth. Characteristics of Pericytes Blood vessels consist of endothelial cells that form the inner lining of the vessel wall and of perivascular cells that wrap around blood vessels. Charles Rouget described perivascular cells more than 100 years ago in amphibia and named them pericytes, i.e., cells that envelop blood capillaries (peri, around; cyte, cell). Pericytes have also been referred to as Rouget cells, mural cells, and, because of their contractile fibers, vascular smooth muscle cells (vSMCs) [1]. A hallmark of pericytes is their location within the basement membrane of capillaries, postcapillary venules, and collecting venules. Pericytes possess a cell body with a prominent nucleus and envelop the abluminal endothelial wall with several of their long cytoplasmic processes (Fig. 4.1) [2]. Thereby, pericytes make focal contacts with numerous endothelial cells through specialized junctions to integrate signals along the length of the vessel, but can also extend to more than one capillary in the vasculature (Fig. 4.1). Gap junctions provide direct connections between the cytoplasm of pericytes and endothelial cells, and they enable the exchange of ions and small molecules. Adhesion plaques anchor pericytes to endothelial cells, while peg-and-socket contacts enable the cells to penetrate through discontinuities in the vessel basement membrane and touch each other [3, 4]. These junction complexes support transmission of mechanical contractile forces from the pericytes to the endothelium and contain N-cadherin, cell-adhesion molecules, ®-catenin-based adherent junctions, and extracellular matrix (ECM) molecules such as fibronectin [5]. Interestingly, cell–cell contact appears necessary for the activation of the latent growth factor TGF-β1, which induces pericyte differentiation in vitro [6], supporting the notion that direct cell contact is a crucial communication tool for vessel maintenance and formation. Identification of Pericytes Besides identifying pericytes by their distinct localization within the vascular basement membrane, pericytes can also be visualized with various dynamic molecular markers that, although not exclusively, detect pericytes in a tissue-specific manner or based on the developmental or angiogenic stage of the organ [7]. Desmin and α-smooth-muscle actin 45 Department of Neurological Surgery, Brain Tumor Research Center and UCSF Comprehensive Cancer Center, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 941430520, USA