Age-related changes in rat myocardium involve altered capacities of glycosaminoglycans to potentiate growth factor functions and heparan sulfate-altered sulfation.

Glycosaminoglycans (GAGs) are essential components of the extracellular matrix, the natural environment from which cell behavior is regulated by a number or tissue homeostasis guarantors including growth factors. Because most heparin-binding growth factor activities are regulated by GAGs, structural and functional alterations of these polysaccharides may consequently affect the integrity of tissues during critical physiological and pathological processes. Here, we investigated whether the aging process can induce changes in the myocardial GAG composition in rats and whether these changes can affect the activities of particular heparin-binding growth factors known to sustain cardiac tissue integrity. Our results showed an age-dependent increase of GAG levels in the left ventricle. Biochemical and immunohistological studies pointed out heparan sulfates (HS) as the GAG species that increased with age. ELISA-based competition assays showed altered capacities of the aged myocardial GAGs to bind FGF-1, FGF-2, and VEGF but not HB EGF. Mitogenic assays in cultured cells showed an age-dependent decrease of the elderly GAG capacities to potentiate FGF-2 whereas the potentiating effect on VEGF(165) was increased, as confirmed by augmented angiogenic cell proliferation in Matrigel plugs. Moreover, HS disaccharide analysis showed considerably altered 6-O-sulfation with modest changes in N- and 2-O-sulfations. Together, these findings suggest a physiological significance of HS structural and functional alterations during aging. This can be associated with an age-dependent decline of the extracellular matrix capacity to efficiently modulate not only the activity of resident or therapeutic growth factors but also the homing of resident or therapeutic cells.

Matrix therapy with RGTA OTR4120 improves healing time and quality in hairless rats with deep second-degree burns.

BACKGROUND: ReGeneraTing Agents (RGTAs) are biodegradable polymers engineered to mimic heparan-sulfate in the extracellular matrix of damaged tissue. RGTAs improve tissue healing in several animal models by stabilizing and protecting heparin-binding growth factors and matrix proteins. RGTA restores the normal matrix architecture and supports tissue regeneration. In this study, the authors evaluated the effects of RGTA on epidermal repair and dermal remodeling in a rat burn model. METHODS: Deep second-degree burns were induced in 156 hairless rats, of which half (n = 78) received topical and intramuscular RGTA immediately after the burn followed by intramuscular RGTA weekly for 1 month. The controls (n = 78) received saline according to the same protocol. Rats were killed starting on each day of the first week and on days 14, 28, 60, 120, 240, and 365. The burns were evaluated by photography, histology, and immunohistochemistry. RESULTS: Coagulation necrosis involved the entire epidermis and superficial adnexa. Compared with the controls, speed of epidermal repair, as assessed between days 3 and 7 based on cell-layer number and anticytokeratin-14 staining, was faster in the RGTA group; and the zone of stasis, as assessed based on secondary vascular lesions in the dermis, was smaller. On day 7, reepithelialization was complete in both groups. On days 14 and 28, the remodeled dermal zone was smaller in the RGTA group. CONCLUSION: RGTA accelerated epidermal repair and protected the dermis from secondary effects of heat as quantified by zone-of-stasis size and extent of dermal remodeling.