We investigate a hypothesis for the generation of nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated Ca2+ waves in the vascular smooth muscle of the pulmonary artery. Agonist-stimulated waves of elevated cytoplasmic calcium concentration regulate blood vessel tone and vasomotion in vascular smooth muscle. In rat pulmonary artery smooth muscle cells, the calcium mobilizing messenger NAADP appears to trigger bursts of Ca2+ release from lysosomal Ca2+ stores by activating the Two Pore Segment Channel subtype 2 (TPC2). It is suggested that these Ca2+ transients initiate a propagating wave by Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs). Deconvolution and confocal microscopy observations, including immunofluorescence, indicate that lysosome clusters may selectively couple to RyR subtype 3 (RyR3) in regions where lysosomes and proximal SR are separated by a narrow space possibly < 100 nm and beyond the resolution of light microscopy. These results naturally lead to the hypothesis that lysosome-SR (L-SR) junctions may form a cytoplasmic trigger zone for the observed Ca2+ bursts and subsequent cell-wide Ca2+ waves. The present study combines prior optical microscopy observations with a thorough ultrastructural characterization of the L-SR junctions in rat pulmonary artery smooth muscle as input data for a quantitative model of the L-SR junction to test the above hypothesis. With this model, we simulate the Ca2+ bursts that may be generated in the L-SR junctions to determine whether or not these bursts give rise to a sufficient increase in junctional [Ca2+] to breach the threshold for RyR3 activation by CICR and thus initiation of a propagating Ca2+ wave.