Loss of the hyaluronan receptor RHAMM prevents constrictive artery wall remodeling

Abstract

Objective Constrictive extracellular matrix (ECM) remodeling contributes significantly to restenosis after arterial reconstruction but its molecular regulation is poorly defined. Hyaluronan (HA) accumulates within ECM at sites of injury where it is thought to facilitate smooth muscle cell (SMC) trafficking and collagen remodeling analogous to its role in cutaneous wound healing. SMC receptors for HA include receptor for hyaluronan-mediated motility (RHAMM), which mediates HA-induced migration. We hypothesized RHAMM would also mediate SMC-matrix interactions to alter extent of constrictive remodeling. Methods We studied the role of RHAMM in SMC attachment to collagen, migration, and contraction of collagen gels using blocking antibodies and SMC from RHAMM−/− knockout mice (rKO). We then determined the role of RHAMM in constrictive artery wall remodeling by comparing changes in wall geometry in rKO versus wild-type +/+ (WT) controls 1 month after carotid ligation. Results HA increased SMC attachment to collagen-coated plates but blocking RHAMM reduced adhesion (p=0.025). rKO SMC also demonstrated reduced adhesion (% adherent: 36.1±2.2 vs. 76.3±1.9, p< 0.05). SMC contraction of collagen gels was enhanced by HA and further increased by RHAMM blockade (p< 0.01) or knockout (gel diameter, mm: rKO, 6.7±0.1 vs. WT, 9.8±0.1, p=0.015). RHAMM promoted constrictive remodeling in vivo as carotid artery size was significantly larger in rKO mice 1 month after ligation. Neointimal thickening however was not affected in rKO (p=NS vs WT) but lumen size was significantly larger (lumen area, μm2: 52.4±1.4 × 103 vs. 10.4±1.8 × 103, p=0.01) because artery size constricted less (EEL area, μm2: rKO, 92.4±4.7×103 vs. WT, 51.3±5.9 × 103, p=0.015). Adventitial thickening and collagen deposition were also more extensive in ligated rKO carotids (adventitial thickness, μm: 218±12.2 vs. 109±7.9, p=0.01). Conclusion HA activation of RHAMM significantly impacts SMC-ECM adhesive interactions and contributes to constrictive artery wall remodeling in mice. Strategies to block RHAMM at sites of vessel injury may prove useful in the prevention of clinical restenosis.

Deletion of Hyaluronan Synthase 3 Inhibits Neointimal Hyperplasia in Mice

“…4, 28 In Rhamm -deficient mice, constrictive artery wall remodeling was reduced after carotid artery ligation improving the lumen caliber, but surprisingly, did not alter the neointimal area itself. 5 Similarly, a role of CD44 in promoting neointimal hyperplasia has been proposed. 29 Though, this has not directly been shown by use of knockout mice.…”

“…4 Lack of RHAMM prevents constrictive vascular remodeling after vessel injury. 5 Therefore, inhibition of interstitial HA synthesis by VSMC appears to be a promising target to inhibit restenosis. 6-8 …”

Scavenger receptor class A member 5 ( SCARA5 ) and suprabasin ( SBSN ) are hub genes of coexpression network modules associated with peripheral vein graft patency

“…Simplistically, one would expect the contraction of vessel size seen with negative remodeling to be associated with increased collagen gel contraction. However, a counter-intuitive inverse relation between collagen gel contraction in vitro and negative arterial remodeling in vivo has also been reported when Rho-kinase or RHAMM are blocked 29, 30 . An explanation of these conflicting results may lie with a mechanoregulation model proposed by Grinnell and colleagues.…”

Hyaluronan and RHAMM in Wound Repair and the “Cancerization” of Stromal Tissues

“…More recently, the role of RHAMM was studied following vessel damage using RHAMM−/− mice [57, 119, 181, 197]. Cell culture studies comparing RHAMM−/− and wild type smooth muscle cells and blocking RHAMM function with antibodies show that RHAMM:HA interactions mediate smooth muscle cell adhesion and contraction of collagen gels.…”