Parathyroid hormone-related protein (PTHrP), a multifunctional peptide that acts as a vasodilator as well as possible regulator of vascular development, is produced in increased amounts in the rheumatoid synovium. To understand whether PTHrP can contribute to the development and function of the rheumatoid microcirculation, studies were undertaken to identify and compare vascular sites of expression of PTHrP and its cognate receptor in the rheumatoid synovium and/or in cultured rheumatoid synovial endothelial cells. Endothelial cells, including apoptotic cells, as determined by TUNEL staining, were the primary site of vascular PTHrP expression in the rheumatoid synovium, a result confirmed in vitro in rheumatoid synovial microvascular endothelial cells. In contrast, the PTH/PTHrP receptor was primarily located in pericytes and smooth muscle cells within the vasculature. These results are consistent with a possible paracrine pathway for PTHrP action in the synovial microcirculation, wherein PTHrP peptides secreted by the synovial endothelium could act on surrounding PTH1R-positive pericytes and smooth muscle cells. (C) 2002 Elsevier Science (USA). All rights reserved.