title: Extracellular matrix remodeling in wound healing of critical size defects in the mitral valve leaflet.
abstract: The details of valvular leaflet healing following valvuloplasty and leaflet perforation from endocarditis are poorly understood. In this study, the synthesis and turnover of valvular extracellular matrix due to healing of a critical sized wound was investigated. Twenty-nine sheep were randomized to either CTRL (n = 11) or HOLE (n = 18), in which a 2.8-4.8 mm diameter hole was punched in the posterior mitral leaflet. After 12 weeks, posterior leaflets were harvested and histologically stained to localize extracellular matrix components. Immunohistochemistry was also performed to assess matrix components and markers of matrix turnover. A semi-quantitative grading scale was used to quantify differences between HOLE and CTRL. After 12 weeks, the hole diameter was reduced by 71.3 ± 1.4 % (p < 0.001). Areas of remodeling surrounding the hole contained more activated cells, greater expression of proteoglycans, and markers of matrix turnover (prolyl 4-hydroxylase, metalloproteases, and lysyl oxidase, each p ≤ 0.025), along with fibrin accumulation. Two distinct remodeling regions were evident surrounding the hole, one directly bordering the hole rich in versican and hyaluronan and a second adjacent region with abundant collagen and elastic fiber turnover. The remodeling also caused reduced delineation between valve layers (p = 0.002), more diffuse staining of matrix components and markers of matrix turnover (p < 0.001), and disruption of the collagenous fibrosa. In conclusion, acute valve injury elicited distinct, heterogeneous alterations in valvular matrix composition and structure, resulting in partial wound closure. Because these changes could also affect leaflet mechanics and valve function, it will be important to determine their impact on healing wounds.
authors.affiliation: Department of Bioengineering, Rice University, PO Box 1892, MS142, Houston, TX, 77251-1892, USA.|Department of Cardiothoracic Surgery, Columbia University School of Medicine, New York, NY, USA.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Stephens
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.|Department of Cardiothoracic and Vascular Surgery, University of Texas Health Science Center, Houston, TX, USA.
authors.forename: Tom C
authors.initials: TC
authors.lastname: Nguyen
authors.affiliation: Department of Bioengineering, Rice University, PO Box 1892, MS142, Houston, TX, 77251-1892, USA.
authors.forename: Jack G
authors.initials: JG
authors.lastname: Blazejewski
authors.affiliation: Department of Bioengineering, Rice University, PO Box 1892, MS142, Houston, TX, 77251-1892, USA.
authors.forename: Dragoslava P
authors.initials: DP
authors.lastname: Vekilov
authors.affiliation: Department of Bioengineering, Rice University, PO Box 1892, MS142, Houston, TX, 77251-1892, USA.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Connell
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Itoh
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.|Laboratory of Cardiovascular Physiology and Biophysics, Palo Alto Medical Foundation, Palo Alto, CA, USA.
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ingels
authors.affiliation: Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: D Craig
authors.initials: DC
authors.lastname: Miller
authors.affiliation: Department of Bioengineering, Rice University, PO Box 1892, MS142, Houston, TX, 77251-1892, USA. grande@rice.edu.
authors.forename: K Jane
authors.initials: KJ
authors.lastname: Grande-Allen
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D008943:Mitral Valve / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D023421:Models, Animal; D012756:Sheep; D013997:Time Factors; D014945:Wound Healing
chemical_list: D015415:Biomarkers; D016326:Extracellular Matrix Proteins
keywords: Collagen; Mitral regurgitation; Mitral valve; Proteoglycans; Wound healing