Endothelial cells (ECs) play a key role in vascular tone modulation by regulating adjacent smooth muscle cell (SMC) contraction in blood vessel walls. Calcium (Ca2+) has a major role in EC functionality, including production of vasoactive substances such as nitric oxide (NO). However, influence of transmembrane potential (Vm) on EC Ca2+ remains controversial. Thus, understanding EC Ca2+ dynamics is indispensable for unlocking vascular tone regulation pathways. The model integrates both EC Ca2+ dynamics and plasmalemmal electrical activity to investigate EC responses to various stimulatory conditions and the interdependency of Ca2+ and Vm. The model, unlike previous modeling efforts, contains a detailed description of plasma membrane electrophysiology. It also includes intracellular Ca2+ handling components and Ca2+-dependent NO production. Most model components were found based on recent EC experimental data or adapted from previous EC models. The model reproduces experimentally observed EC Vm responses to volume-sensitive anion channel inhibitors and to extracellular potassium concentration changes. In addition, simulated Ca2+ transients during agonist stimulation agree qualitatively with experimental data, both under control and Ca2+-activated potassium channel blockade conditions. Model also simulates agonist-induced NO transients in ECs as observed in the literature. Simulations predict volume-sensitive channels as major determinants of resting Vm, and Ca2+ transient profiles being modulated but not determined by Vm. The EC model can assist in the study of SMC-EC interactions and help understand whole vessel autoregulation, both in health and disease. Supported by AHA grant NSDG043506N and Ronald E. McNair Postbaccalaureate Achievement Program.