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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Am+J+Physiol+Cell+Physiol
2014 ; 307
(9
): C878-92
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Pericyte contractility controls endothelial cell cycle progression and sprouting:
insights into angiogenic switch mechanics
#MMPMID25143350
Durham JT
; Surks HK
; Dulmovits BM
; Herman IM
Am J Physiol Cell Physiol
2014[Nov]; 307
(9
): C878-92
PMID25143350
show ga
Microvascular stability and regulation of capillary tonus are regulated by
pericytes and their interactions with endothelial cells (EC). While the RhoA/Rho
kinase (ROCK) pathway has been implicated in modulation of pericyte
contractility, in part via regulation of the myosin light chain phosphatase
(MLCP), the mechanisms linking Rho GTPase activity with actomyosin-based
contraction and the cytoskeleton are equivocal. Recently, the myosin
phosphatase-RhoA-interacting protein (MRIP) was shown to mediate the
RhoA/ROCK-directed MLCP inactivation in vascular smooth muscle. Here we report
that MRIP directly interacts with the ?-actin-specific capping protein ?cap73.
Furthermore, manipulation of MRIP expression influences pericyte contractility,
with MRIP silencing inducing cytoskeletal remodeling and cellular hypertrophy.
MRIP knockdown induces a repositioning of ?cap73 from the leading edge to stress
fibers; thus MRIP-silenced pericytes increase F-actin-driven cell spreading
twofold. These hypertrophied and cytoskeleton-enriched pericytes demonstrate a
2.2-fold increase in contractility upon MRIP knockdown when cells are plated on a
deformable substrate. In turn, silencing pericyte MRIP significantly affects EC
cycle progression and angiogenic activation. When MRIP-silenced pericytes are
cocultured with capillary EC, there is a 2.0-fold increase in EC cycle entry.
Furthermore, in three-dimensional models of injury and repair, silencing pericyte
MRIP results in a 1.6-fold elevation of total tube area due to EC network
formation and increased angiogenic sprouting. The pivotal role of MRIP expression
in governing pericyte contractile phenotype and endothelial growth should lend
important new insights into how chemomechanical signaling pathways control the
"angiogenic switch" and pathological angiogenic induction.