The yin (perlecan) and yang (type XVIII collagen) of angiogenic regulation by heparan sulfate proteoglycans (top panel). Perlecan, syndecans, and glypicans are proposed to act as coreceptors to deliver proangiogenic factors to their high-affinity cell surface receptors. As shown for perlecan, angiogenic stimulation might follow from its increased expression or cell surface accessibility. This would result in release of growth factors such as VEGF, carried by specific heparan sulfate sequences, or FGF2 and FGF7, bound to either heparan sulfate chains or unique regions of the protein core (middle panel). These events promote the cell proliferation phase of angiogenesis and may also trigger the synthesis and release of a battery of proteinases into the ECM milieu. Proteinases in turn would degrade perlecan, thus attenuating its growth-promoting activities, and liberate endostatin from type XVIII collagen (bottom panel). Endostatin is proposed to block VEGF- and FGF-mediated angiogenic signaling, thereby maintaining the endothelium in a quiescent state.