Recent evidence suggests a role for circulating vascular smooth muscle cell (VSMC) progenitors in atherosclerotic plaque biology [1]. Integrins may play a vital role in the homing of these cells to the lesion site [2]. These extracellular matrix (ECM) protein receptors exert an influence over dihydropyridine receptors (DHPRs) [3], primary mediators of calcium (Ca²⁺) influx in differentiated VSMCs, thus presenting a link between alterations of the ECM, cytoplasmic Ca²⁺ ([Ca²⁺]_c) signalling machinery and subsequent cellular responses. The arginine-glycine-aspartic acid (RGD) tripeptide is a well-characterised ligand for several integrin receptors. It has been proposed that the RGD sequence is exposed in many ECM proteins, such as fibrinogen, a marker of cardiovascular disease [4], following tissue damage [5] and therefore influences cell responses by altering Ca²⁺ levels through integrin-mediated DHPR modulation. Specifically, α_vβ₃ integrin-ligand binding inhibits Ca²⁺ current through the DHPRs, whereas α₅β₁ integrin counteracts this response by enhancing current [3]. The current study characterised [Ca²⁺]_c responses of endothelial progenitor cells (EPCs) to RGD tripeptide and fibrinogen exposure, employing fura-2 videomicroscopy. Exposure of EPCs to fibrinogen or tripeptide elicited an initial elevation of [Ca²⁺]_c levels followed by a prolonged decrease relative to resting concentrations, thus implicating both α_vβ₃ and α₅β₁ integrins in this response. Ca²⁺ responses to fibrinogen were abolished by nifedipine, a DHPR blocker. Dantrolene (10μM) and ryanodine (10μM), inhibitors of ryanodine receptors (RyRs), blocked [Ca²⁺]_c increases resulting form integrin-ligand binding, leading to a prolonged decrease in [Ca²⁺]_c levels without recovery of resting levels. Simultaneous incubation of EPCs with nifedipine and ryanodine blocked Ca²⁺ responses to fibrinogen, implying a coupling of function of DHPRs to that of RyRs. To investigate this hypothesis, EPCs were treated with either cytochalasin D (Cyt-D) (10µM), which prevents actin polymerisation, or methyl-β-cyclodextrin (MβCD) (1mM), a cholesterol sequestering agent which disrupts caveoli. Fibrinogen evoked a [Ca²⁺]_c response, similar to that of untreated cells, in Cyt-D-treated EPCs incubated with both nifedipine and ryanodine. MβCD-treated cells did not produce a [Ca²⁺]_c response to fibrinogen. Our laboratories postulate that the biphasic Ca²⁺ response to fibrinogen through integrins in EPCs is a result of RyR modulation to elevate Ca²⁺ levels and the decrease is owed to a functional coupling of RyRs and DHPRs, possibly due to close apposition of the sarcoplasmic reticulum and the plasma membrane.