The pericyte: Cellular regulator of microvascular blood flow

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Abstract

The vascular system – through its development, response to injury, and remodeling during disease – constitutes one of the key organ systems sustaining normal human physiology; conversely, its dysregulation also underlies multiple pathophysiologic processes. Regulation of vascular endothelial cell function requires the integration of complex signals via multiple cell types, including arterial smooth muscle, capillary and post-capillary pericytes, and other perivascular cells such as glial and immune cells. Here, we focus on the pericyte and its roles in microvascular remodeling, reviewing current concepts in microvascular pathophysiology and offering new insights into the specific roles that pericyte-dependent signaling pathways may play in modulating endothelial growth and microvascular tone during pathologic angiogenesis and essential hypertension.

Section snippets

Overview

A complete understanding of the complex regulation of the vascular system requires both a systemic, structural understanding of vascular function, as well as the focused dissection of multiply-intertwined signaling pathways in both vascular and non-vascular cell types (Jain, 2003). While tumor growth is known to depend on concomitant angiogenesis (Folkman, 1971), it has been further suggested that angiogenesis may, in fact, be a common template underlying numerous other disparate phenomena

Pericyte control of microvascular remodeling and proliferative status

The pericyte in particular has drawn increased attention as an emerging key mediator in multiple microvascular processes, including: (i) endothelial cell proliferation and differentiation (Armulik et al., 2005, Hirschi and D'Amore, 1997), (ii) contractility and tone (Herman and D'Amore, 1985, Rucker et al., 2000), (iii) stabilization and permeability (von Tell et al., 2006), and (iv) morphogenesis during disease onset (Yamagishi and Imaizumi, 2005). First described in early studies of vascular

Soluble and trans-matrix extracellular signaling via TGF-beta

The above-described bridging between intracellular signaling and force transduction pathways in pericytes parallels the emerging role for the transforming growth factor-beta (TGF-beta) family of ligands, receptors, and signal-transducing effectors (recently reviewed by Bertolino et al., 2005). In vascular endothelial cells, human analogues of the Drosophila mothers against decapentaplegic (MAD) family of proteins have recently been characterized as primary transducers of TGF-beta signaling

Intracellular signaling via Rho GTPase — smooth muscle cell pathways

Evidence is accumulating that vascular morphogenesis may be regulated by members of the Rho family of small GTPases (as recently reviewed by Bryan and D'Amore, 2007 as well as Mammoto et al., 2008). Rho GTPase-mediated cytoskeletal adaptations modulate normal maintenance of the arterial vasculature, as well as mediate the tone dysregulation and hypertrophic remodeling observed during essential hypertension (Pacaud et al., 2005, Noma et al., 2006, Loirand et al., 2006, Lee et al., 2004). Here,

Intracellular signaling via Rho GTPase — pericyte-specific pathways

The Rho family of small GTPases has long been known to play a role in control of the actin cytoskeleton in many cell types other than vascular smooth muscle (Etienne-Manneville and Hall, 2002). With reference to the above-described pathways, recent work has also demonstrated that similar mechanisms are operative in pericytes. These Rho GTP-dependent (as well as other Rho GTP-independent) pathways function to coordinate pericyte growth and contractile phenotype while simultaneously modulating

Rho signaling in microvascular tone dysregulation

In addition to the role of disrupted endothelial control in vasoproliferative disease, microvascular signaling dysregulation is emerging as a causative factor in the pathogenesis of several non-proliferative vascular pathologies as well. Based on the initial understanding of Rho family GTPase signaling in the regulation of smooth muscle contractility (Hirata et al., 1992), a key role for Rho signaling through Rho kinase has recently been elucidated in both physiological maintenance (Noma et

Conclusions and future directions

Recent work indicates that Rho GTPase and its downstream signaling cascade, previously thought to be confined to vascular smooth muscle cells, have been functionally extended to include the microvascular pericyte. Although the bulk of current literature has investigated the specific nuances of vascular smooth muscle cell-associated and Rho GTPase-dependent signaling, interest is currently developing in the exploration of parallel but distinct roles for Rho signaling in the microvascular

Acknowledgments

We wish to recognize the technical assistance of Lindsey Wolf and Katy Riley, and the parallel experiments of Jennifer Durham. Adenoviral construct assistance and reagents provided by Dr. Howard Surks. Support for this work is partially provided by a Williams Fellowship (MEK) and NIH EY 15125 (IMH).

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    Present address: Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, Room S-321, San Francisco, CA 94143, USA.

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