Restoring Angiogenic Balance in Diabetes: Advanced Molecular Therapeutics for Non-Healing Diabetic Wounds and Cellular Medicines for Diabetic Retinopathy
Sheets, Anthony.
2018
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Abstract: The
microvascular complications of diabetes are associated with a tremendous degree of
morbidity and mortality. Indeed, type I and type II diabetes are leading causes of
adult-onset retinal damage and blindness, non-healing foot ulcers that may require
amputation, and end-stage renal disease around the world. Intriguingly, while these
debilitating conditions arise from long-standing, ... read morehyperglycemia-driven inflammation and
vascular insult, diabetic microangiopathies have strikingly tissue-specific
manifestations: chronic wounds in the extremities of diabetic patients are hallmarked by
their impairments in vascular growth and matrix turnover after injury, whereas
retinopathy is characterized by florid vascular overgrowth that has long been ascribed
to the loss of microvascular pericytes from the retinal circulation. The work performed
in our laboratory and center aims to further elucidate the molecular and cellular
mechanisms of angiogenesis, in order to better understand the pathogenesis of these
diabetes-associated vasculopathies and develop advanced molecular and cellular
therapeutics for these conditions. Linked to these goals, our investigations of
cell-matrix interactions in angiogenesis and wound healing have resulted in the creation
of several bioactive, matrix-derived peptides that induce cellular migration,
proliferation and morphogenesis necessary for tissue repair. And, at the same time, our
studies of pericyte-endothelial interactions reveal that subtle alterations in pericyte
chemo-mechanics - rather than their frank disappearance - may be sufficient to permit
endothelial cell cycle re-entry and angiogenesis. Herein, we demonstrate that bioactive
matrix- and plasma-derived peptides significantly increase re-epithelialization and
angiogenesis in diabetic porcine wounds through upregulation of multiple reparative
growth factors and cytokines, especially matrix metalloproteinases and inhibitors that
may aid in reversing the proteolytic imbalance characteristic of chronically inflamed
non-healing wounds. Additionally, we reveal that Santyl® collagenase induces
post-debridement wound healing through the liberation of bioactive matrix-derived
peptides within the wound bed, and that a "combinatorial" peptide created from some of
the individual matrix domains fosters wound healing in vivo at a dose equivalent to that
of Santyl®. Finally, as an extension of our studies of RhoGTPase in the regulation
of pericyte chemo-mechanical control of angiogenesis, we show that key perturbations in
the downstream pericyte RhoGTPase effectors, LIM-kinases and cofilin, promote
endothelial cell cycle re-entry that may contribute to the development of vascular
proliferative lesions in diabetic retinopathy. Overall, our findings should inform the
development of next-generation molecular and cellular therapeutics capable of repairing
difficult-to-heal wounds and abrogating or ameliorating pathologic neovascularization in
diabetic retinopathy.
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Cellular & Molecular Physiology.
Advisor: Ira Herman.
Committee: Brent Cochran, Guofu Hu, and Harold Dvorak.
Keywords: Medicine, Biology, and Surgery.read less - ID:
- jw827p65m
- Component ID:
- tufts:25452
- To Cite:
- TARC Citation Guide EndNote
