Modulation of microvascular signaling by heparan sulfate matrix: Studies in syndecan-4 transgenic mice

The onset of tissue ischemia is associated with significant changes in the expression of heparan sulfate- (HS) carrying core proteins that, in turn, lead to alterations in composition of the extracellular HS matrix. Since HS can bind numerous growth factors and cytokines, such changes in the HS matrix content can have profound effects on the ability of these factors to interact with their target cells. To investigate the role of increased HS matrix content on microvascular function, we used a-myosin heavy chain (MHC promoter to overexpress a HS-carrying core protein, syndecan-4, in cardiac myocytes in mice. Mice expressing the transgene (alphaMHC-S4) demonstrated a significant increase in nitric oxide (NO) release in the coronary effluent in response to fibroblast growth factor 2 (FGF2, 1 mug/mL administration despite similar expression levels of NO synthase genes 11 and III (iNOS and eNOS, respectively). In vitro studies of coronary microvessels derived from aMHC-S4 mice demonstrated increased relaxation response to FGF2 compared to control mice, At the same time, vasodilator response to adenosine diphosphate (ADP) was significantly impaired in alphaMHC-S4 mice-derived microvessels. Addition of exogenous HS to microvessels derived from control mice enhanced FGF2-induced vasodilation while inhibiting ADP- induced vasomotion. The vasomotor activity of the enclothelial receptor-independent agent (A23187) and the endothelium-independent agent (sodium nitroprusside) was not affected by heparan sulfate. These results demonstrate that alterations in HS production have a profound and heterogeneous effect on endothelial receptor-dependent vasodilators. and point to a novel role of the HS matrix in regulation of microvascular homeostasis. (C) 2002 Elsevier Science (USA).