Molecular Mediators of Angiogenesis

Ucuzian, Areck A.; Gassman, Andrew; East, Andrea T.; Greisler, Howard P.

doi:10.1097/bcr.0b013e3181c7ed82

Cited by 380 publications

(283 citation statements)

References 262 publications

(206 reference statements)

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“…Laser speckle contrast imaging demonstrated graft perfusion as early as post-operative day 5, even before complete epithelialization of skin graft interstices. This is consistent with animal skin grafting research demonstrating the early perfusion of human skin transplanted onto athymic mice via the process of inosculation, the fusion or anastomosis of two vascular lumens to form one continuous lumen [20] [21]. Visceral graft perfusion plateaued during post-operative weeks 2 -3 and did not change thereafter, suggesting that graft separation from underlying viscera was not initiated by changes in local perfusion.…”

Section: Discussionsupporting

confidence: 68%

Investigation of Open Abdomen Visceral Skin Graft Revascularization and Separation from Peritoneal Contents

Clark¹,

Coffman²,

Brandenburg³

et al. 2018

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Background: Despite increasing survival following damage control laparotomy and open abdomen technique, little is known about the biology of visceral skin graft revascularization and separation from peritoneal contents. Methods: Following laparotomy for trauma, patients with visceral edema preventing fascial closure underwent Vicryl mesh closure followed by visceral split-thickness skin grafting and readmission graft excision and abdominal wall reconstruction. Utilizing laser speckle contrast imaging, immunochemical staining of histologic sections, and RT-PCR array technology, we examined the revascularization, microvascular anatomy, morphology, and change in gene expression of visceral skin grafts. Results: Ten patients ranging in age from 25 to 46 years underwent visceral grafting for cutaneous coverage of an open abdomen. Skin graft perfusion peaked at a mean of 350 PU by post-operative day 14 synchronous with closure of meshed interstices, and remained constant until excision. Time to graft excision ranged from 6 to 18 months. CD-31 immunostaining documented a significant (p = 0.04) increase in vascular surface area in excised grafts compared to control skin. Trichrome staining revealed an 8-fold increase in excised graft thickness. Mesothelial cells were identified within the dermal matrix of excised grafts. RT-PCR demonstrated significant up-regulation of genes involved in matrix structure and remodeling, cytoskeleton regulation, and WNT signaling; and down-regulation of genes involved in inflammation and matrix proteolysis in excised grafts compared to control skin. Conclusion: Our data document early visceral skin graft perfusion and a plateau in revascularization. Histology reveals a robust dermal matrix populated by fibroblasts and mesothelial cells within a complex supporting vascular network. Genetic analysis of excised grafts reveals growth factor, collagen, and matrix remodeling gene expression.

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Section: Discussionsupporting

confidence: 68%

Investigation of Open Abdomen Visceral Skin Graft Revascularization and Separation from Peritoneal Contents

Clark¹,

Coffman²,

Brandenburg³

et al. 2018

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“…Collectively, these results suggest that Angiopoietin signaling, via the Tie2 and AKT pathways, mediates VIC-VEC organization, as well as evolution towards invasive angiogenic behavior. This finding is significant due to the role of Ang-Tie2 signaling in initial vascular destabilization, 33 and therefore suggests a role for this pathway in initial VEC dysfunction during the early pathology of CAVD. Further studies are required to confirm the role and source of Tie2 signaling activity and its effects on VEC monolayer homeostasis during CAVD.…”

Section: Discussionmentioning

confidence: 81%

Valve Interstitial Cells Act in a Pericyte Manner Promoting Angiogensis and Invasion by Valve Endothelial Cells

et al. 2016

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Neovascularization is an understudied aspect of calcific aortic valve disease (CAVD). Within diseased valves, cells along the neovessels' periphery stain for pericyte markers, but it is unclear whether valvular interstitial cells (VICs) can demonstrate a pericyte-like phenotype. This investigation examined the perivascular potential of VICs to regulate valve endothelial cell (VEC) organization and explored the role of Angiopoeitin1-Tie2 signaling in this process. Porcine VECs and VICs were fluorescently tracked and co-cultured in Matrigel over 7 days. VICs regulated early VEC network organization in a ROCK-dependent manner, then guided later VEC network contraction through chemoattraction. Unlike vascular control cells, the valve cell cultures ultimately formed invasive spheroids with 3D angiogenic-like sprouts. VECs co-cultured with VICs displayed significantly more invasion than VECs alone; with VICs generally leading and wrapping around VEC invasive sprouts. Lastly, Angiopoietin1-Tie2 signaling was found to regulate valve cell organization during VEC/VIC spheroid formation and invasion. VICs demonstrated pericyte-like behaviors toward VECs throughout sustained co-culture. The change from a vasculogenic network to an invasive sprouting spheroid suggests that both cell types undergo phenotypic changes during long-term culture in the model angiogenic environment. Valve cells organizing into spheroids and undergoing 3D invasion of Matrigel demonstrated several typical angiogenic-like phenotypes dependent on basal levels of Angiopoeitin1-Tie2 signaling and ROCK activation. These results suggest that the ectopic sustained angiogenic environment during the early stages of valve disease promotes organized activity by both VECs and VICs, contributing to neovessel formation and the progression of CAVD.

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“…Other chemical signals that play an important role in angiogenesis are fibroblast growth factor, HGF, tumor necrosis factor-alpha (TNF-), transforming growth factor-beta (TGF-), angiopoietins, and platelet derived growth factor (PDGF). The function of these signals ranges from involvement in extracellular matrix degradation to endothelial proliferation and migration and then ultimately to neo-vessel stabilization and maturation (Martin and Jiang 2010;Ucuzian, Gassman et al 2010). …”

Section: Molecular Signals Of Angiogenesis Vegfmentioning

confidence: 99%