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Xue Ma, MD, Jeffrey D. Pearce, MD, David B. Wilson, MD, William P

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1 Loss of the hyaluronan receptor RHAMM prevents constrictive artery wall remodeling 
Xue Ma, MD, Jeffrey D. Pearce, MD, David B. Wilson, MD, William P. English, MD, Matthew S. Edwards, MD, Randolph L. Geary, MD  Journal of Vascular Surgery  Volume 59, Issue 3, Pages (March 2014) DOI: /j.jvs Copyright © 2014 Society for Vascular Surgery Terms and Conditions

2 Fig 1 Constrictive remodeling following arterial reconstruction. In this example, a 17% decrease in outer artery wall caliber from 3.0 to 2.5 U, with cross-sectional wall area held constant, reduces lumen area by 68% from 3.1 to 0.9 U2. L, Lumen; U, arbitrary unit. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

3 Fig 2 Receptor for hyaluronan-mediated motility (RHAMM) messenger RNA and protein expression in aortic smooth muscle cells (SMCs) cultured from wild-type (WT) RHAMM +/+ and RHAMM −/− knockout mice measured with reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot. GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

4 Fig 3 Chart shows the number of cells adherent to plastic coated with either type-I collagen alone or collagen with hyaluronan (HA). Adherent cell number expressed as percent of total smooth muscle cells (SMCs) loaded per well. HA increased adhesion by 35.5 ± 1.9% compared with collagen alone (**P = .01; n = 4), and knocking out hyaluronan-mediated motility (RHAMM) significantly reduced adhesion to both matrix coatings (n = 4 independent experiments; *P < .05). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

5 Fig 4 Scratch wound migration assay. A, Photomicrographs show representative scratch wounds, acutely and then 48 hours later for smooth muscle cells (SMCs) treated with control IgG (above) or antireceptor for hyaluronan-mediated motility (RHAMM) blocking antibody (below). RHAMM blockade inhibited migration into scratch wounds, whereas control wounds were nearly confluent at 48 hours. B, Bar chart showing % area healed by wild-type (WT) RHAMM +/+ and RHAMM −/− knockout SMCs. Loss of RHAMM expression significantly reduced extent of migration into scratch wound of confluent SMC culture compared with WT controls at 48 hours. (**P = .01; n = 4). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

6 Fig 5 Collagen gel contraction assay. A, Photograph of a series of collagen gels with and without hyaluronan (HA) floating in media (dashed outline). Collagen-I alone (top row) and with HA (bottom row) seeded with wild-type (WT) hyaluronan-mediated motility (RHAMM) +/+ smooth muscle cells (SMCs). HA enhanced contraction of collagen resulting in smaller gel diameter at 18 hours. B, Line chart summarizes mean gel diameter ± standard deviation (SD) at each time point for WT SMC in collagen (○), vs collagen with HA (□), and for RHAMM −/− knockout SMC in collagen (●), vs collagen + HA (■). Data represent mean ± SD from six independent experiments. C, Bar chart compares final gel diameter at 18 hours. Loss of RHAMM significantly increased contraction (smaller gel diameter, *P = .015; **P < .01; n = 6). Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

7 Fig 6 Pericellular accumulation of collagen fibers. Collagen fibers at the surface of smooth muscle cells (SMCs) was measured in gels at 18 hours, expressed as image area occupied by picrosirius red-stained fibers viewed under polarized light. Condensation was enhanced around hyaluronan-mediated motility (RHAMM) −/− knockout compared with wild-type (WT) RHAMM +/+ SMCs. Data are mean ± standard deviation (SD) of 100 cells imaged from each condition. *P < .05. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

8 Fig 7 Carotid artery histology and morphometry. A, Upper panel shows artery wall architecture (adventitia, media, intima) in unligated (control) carotid arteries of wild-type (WT) hyaluronan-mediated motility (RHAMM) +/+ and RHAMM −/− knockout mice, which was normal and similar for both 28 days after contralateral carotid ligation. Bottom panel shows ligated carotid arteries for both groups. WT mice demonstrated more shrinkage of the ligated artery wall and lumen (constrictive remodeling) than RHAMM −/− mice. B, Morphometry data for the ligated arteries from each group are summarized in bar charts. Knockout mice (n = 16) demonstrated significantly thicker adventitia, larger artery (EEL area), and larger lumen area but not difference in neointimal hyperplasia. A, Adventitia; EEL, external elastic lamina; IEL, internal elastic lamina; L, lumen; N, neointima. **P ≤ .01. All panels, ×200 magnification. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

9 Fig 8 Collagen and hyaluronan (HA) deposition 28 days after carotid ligation in wild type (WT) mice. A, HA (brown staining) accumulated in neointima and adventitia of ligated compared with unligated carotid arteries (control). B, Picrosirius red staining for collagen fibers viewed under brightfield (red staining, top) and polarized light (darkfield, bottom) in unligated control and ligated carotid arteries shows significant collagen fiber condensation in the adventitia of ligated arteries after 28 days. All panels, ×200 magnification. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

10 Fig 9 Picrosirius staining of adventitial collagen in both wild-type (WT) hyaluronan-mediated motility (RHAMM) +/+ and RHAMM −/− knockout arteries 28 days following ligation, quantified using thresholding of digital images viewed under polarized light. Collagen fiber density was higher in knockout mice (n = 16) compared with WT controls (n = 13). *P < .05. ROI, Region of interest. Journal of Vascular Surgery  , DOI: ( /j.jvs ) Copyright © 2014 Society for Vascular Surgery Terms and Conditions

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