Inhibition of canonical Wnt signaling increases microvascular hemorrhaging and venular remodeling in adult rats.
OBJECTIVE
The canonical Wnt signaling pathway, heavily studied in development and cancer, has recently been implicated in microvascular growth with the use of developmental and in vitro models. To date, however, no study exists showing the effects of perturbing the canonical Wnt pathway in a complete microvascular network undergoing physiological remodeling in vivo. Our objective was to investigate the effects of canonical Wnt inhibition on the microvascular remodeling of adult rats.


METHODS
Canonical Wnt inhibitor DKK-1, Wnt inhibitor sFRP-1, BSA or saline was superfused onto the exteriorized mesenteric windows of 300 g adult female Sprague-Dawley rats for 20 minutes. Three days following surgery, mesenteric windows were imaged intravitally and harvested for immunofluorescence staining with smooth muscle alpha-actin and BRDU.


RESULTS
We observed prominent differences in the response of the mesenteric microvasculature amongst the various treatment groups. Significant increases in hemorrhage area, vascular density, and draining vessel diameter were observed in windows treated with Wnt inhibitors as compared to control-treated windows. Additionally, confocal imaging analysis showed significant increases in proliferating cells as well as evidence of proliferating smooth muscle cells along venules.


CONCLUSIONS
Together, our results suggest that canonical Wnt inhibition plays an important role in microvascular remodeling, specifically venular remodeling.
Glaw
Jason T
JT
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia 22908, USA.
Skalak
Thomas C
TC
Peirce
Shayn M
SM
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006470:Hemorrhage / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology; D008565:Membrane Proteins / Q000494:pharmacology / Q000502:physiology; D008642:Mesenteric Veins / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology*; D008955:Models, Cardiovascular; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014699:Venules / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; D051153:Wnt Proteins; C531384:Dkk1 protein, rat; C500646:Sfrp1 protein, rat; D000094742:Secreted Frizzled-Related Proteins