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Review: Endothelial Extracellular Matrix
Review: Endothelial Extracellular Matrix
Review: Endothelial Extracellular Matrix
This Review is part of a thematic series on Vascular Cell Diversity, which includes the following articles:
Heart Valve Development: Endothelial Cell Signaling and Differentiation
Molecular Determinants of Vascular Smooth Muscle Cell Diversity
Endothelial/Pericyte Interactions
Endothelial Extracellular Matrix: Biosynthesis, Remodeling, and Functions During Vascular Morphogenesis and
Neovessel Stabilization
Joyce Bischoff, Guest Editor
vessel stabilization, all of which are critical for neovascularization. The specific mechanisms through which ECM supports EC functions are complex and involve both external
structural support and regulation of multiple signaling pathways within the cell, including signaling pathways that
control apoptosis, proliferation, the cytoskeleton, and cell
shape. Thus, through both mechanical and signaling func-
Original received June 23, 2005; revision received October 3, 2005; accepted October 11, 2005.
From the Department of Pathology (G.E.D.), Texas A&M University System Health Science Center, College Station; and Department of Pathology
(D.R.S.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Mass.
Correspondence to Donald R. Senger, Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Research North,
99 Brookline Ave, Boston, MA 02215. E-mail dsenger@bidmc.harvard.edu
2005 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/01.RES.0000191547.64391.e3
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a process involving development and coalescence of intracellular vacuoles.26 In sharp contrast to ECs, fibroblasts do not
respond to collagen I with changes in cell shape or alignment
into cords, suggesting a special connection between collagen
I signaling and EC morphogenesis.32
In support of the importance of interstitial collagens in
driving ECs to form precapillary cords, there is much evidence that interactions between interstitial collagens and ECs
are highly relevant in vivo. During sprouting angiogenesis,
ECs within existing blood vessels degrade basement membrane33 and migrate and proliferate within connective tissue
abundant in interstitial collagens.34 Furthermore, the key
angiogenic cytokine VEGF, which induces sprouting angiogenesis also induces microvascular ECs to express integrins
11 and 21,35 which are the key interstitial collagen
receptors on microvascular ECs. Moreover, antagonism of
these integrins inhibits dermal and tumor angiogenesis in
vivo.3,35 Also, analyses of genes expressed in human tumor
endothelium have demonstrated that ECs isolated from tumors express 10-fold more transcripts encoding interstitial
collagens type I and III than ECs isolated from corresponding
control tissue, indicating that tumor ECs express their own
interstitial collagens,36 thus suggesting that interstitial collagen expression by tumor ECs may be conducive for angiogenesis. In support of this hypothesis, expression of collagen
I by isolated EC clones in vitro correlates with spontaneous
multicellular organization of these ECs into cords.37,38 Finally, neovascularization can be inhibited in animal models
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both by proline analogues that interfere with collagen triplehelix assembly and by -aminopropionitrile, which inhibits
collagen cross-linking,39 indicating that collagens play a
crucial role in angiogenesis.
Recently, the mechanisms through which collagen I selectively provokes EC formation of cord-like structures that
closely imitate precapillary cords in vivo have begun to be
identified. First, collagen I-ligation of integrins 11 and 21
in microvascular ECs in vitro suppresses cAMP and thereby
suppresses the activity of cAMP-dependent protein kinase A
(PKA). Suppression of PKA activity leads to a marked
induction of actin polymerization that contributes to the
formation of prominent stress fibers and EC contractility.
Suppression of PKA and induction of actin polymerization
closely parallel cord formation in vitro, consistent with
functional significance. In contrast to collagen I, laminin-1
neither suppresses cAMP nor PKA activity nor induces actin
polymerization, indicating specificity among matrix proteins
regarding this signaling pathway.32 Consistent with the importance of this pathway for formation of precapillary cords,
laminin-1 also failed to induce changes in cell shape. Moreover, in contrast to ECs, fibroblasts did not respond to
collagen I with changes in cAMP or actin polymerization,
consistent with the failure of collagen I to provoke cord
formation by fibroblasts. Pharmacological elevation of cAMP
blocks collagen-induced actin polymerization and formation
of cords by ECs; conversely, pharmacological suppression of
either cAMP or PKA induces actin polymerization. Thus,
collagen Iinduced suppression of cAMP-dependent PKA
and induction of actin polymerization is an important mechanism through which collagen I drives EC organization into
multicellular precapillary cords.32
In addition to suppressing cAMP-dependent PKA, collagen
I stimulation of microvascular ECs in vitro induces activation
of Src kinase and the GTPase Rho, also through interactions
with 1 integrins.40 Similar to suppression of PKA, activation
of Src and Rho parallels cord formation. The Src inhibitor
PP2, dominant-negative Src, the Rho inhibitor exoenzyme C3
transferase, and dominant-negative RhoA each individually
inhibit collagen I induction of actin stress fibers that mediate
cell retraction, and each inhibit capillary morphogenesis.40,41
Thus, collagen I induces actin stress fibers through activation
of Src and Rho,40 and such activation likely complements
collagen Iinduced actin polymerization, as mediated by
PKA suppression (see above), to achieve the robust cytoskeletal contractility that drives cord assembly. Importantly, the
significance of actin stress fibers and EC contractility for
angiogenesis in vivo has been established in a mouse model
of VEGF-driven neovascularization. Specifically, retrovirusmediated transduction of ECs with a dominant-negative
RhoA mutant that blocks EC contractility and cord formation
in vitro markedly suppressed organization of proliferating
ECs into new blood vessels in vivo.41
Activation of Src by collagen I not only contributes to the
formation of actin stress fibers but also disrupts vascular
endothelial (VE)-cadherin from intercellular junctions. Both
the Src inhibitor PP-2 and dominant-negative Src preserve
VE-cadherin localization to regions of cell cell contact; in
the absence of such inhibitors, VE-cadherin is disrupted by
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Figure 3. Fundamental contribution of the ECMintegrin cytoskeletal signaling axis to the assembly of EC cords as well as formation
of lumens and tubular networks during vasculogenesis and angiogenesis. In this schematic, 2 models of EC morphogenesis are illustrated. a, Confluent human EC monolayers were overlaid with a type I collagen gel and allowed to undergo cord formation, illustrating
how collagenous ECM markedly converts an EC monolayer to an interconnecting network of cords. This process is dependent on the
11 and 21 integrins and the small GTPase RhoA. Right (b), Human ECs are suspended as individual cells in 3D collagen matrices
and are fixed, stained, and photographed at 8 and 48 hours of culture, illustrating intracellular vacuoles and early lumen formation at 8
hours and interconnecting networks of EC-lined tubes at 48 hours. Bar50 m. The 3 panels on the far right (c) are cross-sections
from plastic-embedded collagen gels revealing EC intracellular vacuoles (top and middle right) or EC lumens (bottom right).
Bar25 m. The vacuole and lumen formation process shown is completely dependent on the 21 integrin and the Cdc42 and Rac1
small GTPases.
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Acknowledgments
This work was supported by NIH grants HL59373 and HL79460 (to
G.E.D.), NIH grant CA77357 (to D.R.S.), and grants from the V.
Kann Rasmussen Foundation (to D.R.S.).
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Online Table 1. Vascular defects in mouse knockouts of ECM basement membrane matrix genes
Basement membrane
component
Laminin 4 chain
(laminin-8)
Laminin 5 chain
(laminin-10)
Perlecan
Nidogens 1 and 2
References