Background
Hyperoxia has been shown to improve wound healing; however, the mechanism for such
therapeutic effects of oxygen remains hypothetical. Rac 1 regulates a wide variety
of cellular activities, including cell proliferation and migration, and also is a
key regulator for the activity of the nicotinamide dinucleotide phosphate oxidase
the enzyme complex responsible for the production of a large fraction of cellular
superoxide.
Methods
We generated transgenic mice that express either the cDNA of a constitutively active
mutant of human Rac 1 (V12 mutant or Rac CA) or the dominant negative isoform (V12
and N17 mutant or Rac DN) in the blood vessels using mouse vascular smooth muscle
promoter for α-actin. We placed 2 wounds of 6 mm in diameter at the middorsal region
of each mouse and allowed about 3 weeks for the wounds to heal.
Results
The size of the wounds in Rac CA transgenic mice was reduced relative to wild type
mice; healing of Rac DN mice was slower than wild type and Rac CA (P < .05). Blood vessel formation appeared faster in Rac CA mice, a finding associated
with enhanced expression of some angiogenic growth factors.
Conclusion
The current studies suggest that Rac 1 activation accelerates the wound healing process
and is associated with more efficient angiogenesis at the wound site.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to SurgeryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Cutaneous tissue repair:basic biologic consideration.I J Am Acad Dermatol. 1985; 13: 701-725
- The modern approach to wound treatment.Med Pregl. 2000; 53: 363-368
- Rac, superoxide, and signal transduction.in: Sen C.K. Sies H. Baeuerle P.A. Antioxidant and redox regulation of genes. Academic Press, 2000: 47-79
- Effects of mechanical strain on gastric cellular migration and proliferation during mucosal healing: role of Rho dependent and Rac dependent cytoskeletal reorganization.Gut. 1999; 45: 508-515
- Growth factors in wound healing: single and synergistic effects on partial thickness porcine skin wounds.J Clin Invest. 1989; 84: 640-646
Hassanain HH, Rauscher FM, Marcelo ML, Selvakumar B, Gregg D, Ma Q, et al. Hypertension caused by transgenic overexpression of Rac1 (Hypertension) (Revised for publication to Circulation).
- The 5′-flanking region of the mouse vascular smooth muscle alpha-actin gene contains evolutionarily conserved sequence motifs within a functional promoter.J Biol Chem. 1990; 265: 16667-16675
- Plasticity of vascular smooth muscle α-actin gene transcription.J Biol Chem. 1995; 270: 11310-11321
- Isolation and characterization of the mouse cardiac myosin heavy chain genes.J Biol Chem. 1991; 266: 9180-9185
- Manipulating the mouse embryo: a laboratory manual.Cold Spring Harbor Laboratory, New York1986 (p. 17-77)
- Alterations of p53 and MDM-2 genes are infrequent in clinically localized, stage B prostate adenocarcinoma.Am J Path. 1994; 145: 287-293
- Antibodies: a laboratory manual.Cold Spring Harbor Laboratory, New York1988 (p. 481-2)
- Mammary localization and abundance of laminin, fibronectin, and collagen IV.J Dairy Sci. 2003; 86: 2864-2874
- The activated mesangial cell: a glomerular “myofibroblast”?.J Am Soc Nephrol. 1992; 2: S190-S197
- Rho GTPases control polarity, protrusion and adhesion during cell movement.J Cell Biol. 1999; 144: 1235-1244
- The small GTP-binding protein Rac regulates growth factor-induced membrane ruffling.Cell. 1992; 70: 401-410
- Hypoxia-regulated gene expression in fatal wound regeneration and adult wound repair.Pediatr Surg Int. 2000; 16: 232-236
- Growth factors in wound healing. Single and synergistic effects on partial thickness porcine skin wounds.J Clin Invest. 1989; 84: 640-646
- Neuronal defects and delayed wound in mice lacking fibroblast growth factor 2.Proc Natl Acad Sci USA. 1998; 95: 5672-5677
- Blood vessels fibronectin increases in conjunction with endothelial cell proliferation and capillary ingrowth during wound healing.J Invest Dermatol. 1998; 79: 269-276
- Early wound healing exhibits cytokine surge without evidence of hypoxia.Ann Surg. 2000; 231: 137-147
- Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.Mol Cell Biol. 1996; 16: 4604-4613
- Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia.J Biol Chem. 1997; 28: 272-275
- Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1.J Biol Chem. 1996; 271: 32529-32537
- Structural and functional analysis of hypoxia-inducible factor 1.Kidney Int. 1997; 51: 553-555
- Isoforms of vascular endothelial growth factor act in a coordinate fashion to recruit and expand tumor vasculature.Mol Cell Biol. 2000; 20: 7282-7291
- Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1.Science. 1999; 286: 2511-2514
- Expression of alpha-smooth muscle actin, TGF-beta and TGF-beta type II receptor during connective tissue contraction.In Vitro Cell Dev Biol Anim. 1997; 33: 622-627
- Vanadate and the absence of myofibroblasts in wound contraction.Arch Surg. 1999; 134: 494-501
- Angiogenesis in wound repair: angiogeneic growth factors and extracellular matrix.Microsc Res Tech. 2003; 60: 107-114
- Collagen type IV: major component of basement membranes: current knowledge.Ann Biol Clin. 1990; 48: 695-711
- Hypoxia modulates the effects of transforming growth factor-beta isoforms on matrix-formation by primary human lung fibroblasts.Cytokine. 2003; 24: 25-35
- Activation of the NADPH oxidase involves the small GTP-binding protein p21rac1.Nature. 1991; 353: 668-670
- The actin cytoskeleton reorganization induced by Rac 1 requires the production of superoxide.Antioxid Redox Signal. 1999; 1: 29-43
- Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts.Science. 1997; 275: 1649-1652
- Phosphatidylinositol-3 kinase dependent pathways: the role in control of cell growth, survival, and malignant transformation.Biochemistry. 2000; 65: 59-67
- Rac is essential in the transformation of endothelial cells by polyoma middle virus.Cell Adhes Commun. 2000; 7: 409-422
- Rac regulates the stability of the adherens junction and its components, thus affecting epithelial cell differentiation and transformation.Oncogene. 1999; 18: 6434-6442
- Differential roles of Akt, Rac, and Ral in R-Ras-mediated cellular transformation, adhesion, and survival.Mol Cell Bio. 1999; 19: 6333-6344
- Specific contributions of the small GTPases Rho, Rac, and Cdc42 to Dbl transformaton.J Biol Chem. 1999; 274: 23633-23641
- Plant Rac proteins induce superoxide production in mammalian cells.Biochem Biophys Res Commu. 2000; 272: 783-788
- How do fibroblasts interact with the extracellular matrix in wound contraction?.J Wound Care. 2001; 10: 237-242
- Understanding the final stages of wound contraction.J Wound Care. 2001; 10: 259-264
- Small GTP-binding proteins and the regulation of the actin cytoskeleton.Annu Rev Cell Biol. 1994; 10: 31-54
- Rho GTPases and signaling networks.Genes Dev. 1997; 11: 2295-2322
- Vanadate and the absence of myofibroblasts in wound contraction.Arch Surg. 1999; 134: 494-501
- Expression of alpha-smooth muscle actin, TGF-beta and TGF-beta type II receptor during connective tissue contraction.In Vitro Cell Dev Biol Anim. 1997; 33: 622-627
Article info
Publication history
Accepted:
June 8,
2004
Columbus, Ohio, and Durham, NCIdentification
Copyright
© 2005 Elsevier Inc. Published by Elsevier Inc. All rights reserved.