June 2013
Volume 54, Issue 15
ARVO Annual Meeting Abstract  |   June 2013
Manipulating Pericyte Contractility Alters Endothelial Growth and Angiogenic Potential
Author Affiliations & Notes
  • Jennifer Durham
    Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, MA
  • Ira Herman
    Molecular Physiology and Pharmacology, Tufts University School of Medicine, Boston, MA
  • Footnotes
    Commercial Relationships Jennifer Durham, None; Ira Herman, HealthPoint Biotherapeutics (C), Wound Care Partners LLC (I)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2013, Vol.54, 5571. doi:
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      Jennifer Durham, Ira Herman; Manipulating Pericyte Contractility Alters Endothelial Growth and Angiogenic Potential. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5571.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Diabetic retinopathy continues to be the leading cause of adult-onset blindness, globally. Photocoagulation therapies destroy pathologic vessels through laser ablation, yet pose risks for retinal detachment, while chronic anti-VEGF treatment may impair neural retinal survival/function. Thus, it is imperative to divulge mechanisms driving pathologic angiogenesis, to discover innovative medicines capable of preventing/protecting retinal function by promoting microvascular stability. To these ends, we investigated the role of retinal pericyte (RP) contractility on retinal endothelial cell (REC) dynamics and angiogenic potential.

Methods: As the myosin-phosphatase RhoA interacting protein, MRIP, has been shown to regulate the RhoA/ROCK mediated inactivation of the myosin phosphatase and muscle cell contractility, we employed siRNA to silence MRIP in RP. We combined 2D and 3D co-culture based approaches in combination with biophysical, biochemical and high-resolution imaging to assess the role of RhoGTP and cytoskeletal effectors in modulating RP-REC interactions and angiogenic activation in vitro.

Results: MRIP silencing induces RP hypertrophy including stress fiber assembly with increased isoactin incorporation/expression. MRIP-silencing also induces a marked enhancement in force generation since there is a 2.2 fold increase in substrate deformation. When MRIP-silenced RP are co-cultured with REC there is a ~2.5 fold increase in endothelial cell cycle re-entry. Similarly, MRIP-silenced RP induce a 1.5 fold increase in angiogenic sprouting when cells are placed together in a 3D model of angiogenesis.

Conclusions: Altering RP contractile phenotype via manipulation of the Rho GTP cytoskeletal effector pathway markedly promotes angiogenesis, in part, by stimulating endothelial cell-cycle re-entry and angiogenic sprouting. Thus, subtle changes in RP mechanochemistry could represent key, initiating events in re-activating REC proliferation, promoting diabetes-induced, pathologic angiogenesis. In turn, this paradigm-shifting hypothesis suggests a mechanical component to the ‘angiogenic switch’ and calls into question whether pericyte loss/dropout is required for ocular pathologic angiogenic induction. Furthermore, we envision that manipulating RP cytoskeletal effector function could represent an innovative cell-based therapy for preventing and/or protecting retinal function during diabetes.

Keywords: 493 cytoskeleton • 499 diabetic retinopathy  

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