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An increase in intracellular Ca2+ concentration ([Ca2+]i) is the main mechanism whereby vascular endothelial cells integrate the information conveyed by local and circulating cues. Herein, we describe the dynamics and spatial distribution of endothelial Ca2+ signals to understand how an array of spatially restricted (at both the subcellular and cellular levels) Ca2+ signals is exploited by the vascular intima to fulfill this complex task. We then illustrate how local endothelial Ca2+ signals affect the most appropriate vascular function and are integrated to transmit this information to more distant sites to maintain cardiovascular homeostasis. Vasorelaxation and sprouting angiogenesis were selected as an example of functions that are finely tuned by the variable spatio-temporal profile endothelial Ca2+ signals. We further highlighted how distinct Ca2+ signatures regulate the different phases of vasculogenesis, i.e., proliferation and migration, in circulating endothelial precursors.<\/jats:p>","DOI":"10.3390\/ijms242316765","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T03:32:03Z","timestamp":1701055923000},"page":"16765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Cracking the Endothelial Calcium (Ca2+) Code: A Matter of Timing and Spacing"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0010-0098","authenticated-orcid":false,"given":"Francesco","family":"Moccia","sequence":"first","affiliation":[{"name":"Laboratory of General Physiology, Department of Biology and Biotechnology \u201cL. Spallanzani\u201d, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Brunetti","sequence":"additional","affiliation":[{"name":"Laboratory of General Physiology, Department of Biology and Biotechnology \u201cL. Spallanzani\u201d, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7728-6815","authenticated-orcid":false,"given":"Teresa","family":"Soda","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Magna Graecia, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4884-0925","authenticated-orcid":false,"given":"Roberto","family":"Berra-Romani","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, School of Medicine, Benem\u00e9rita Universidad Aut\u00f3noma de Puebla, Puebla 72410, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Scarpellino","sequence":"additional","affiliation":[{"name":"Laboratory of General Physiology, Department of Biology and Biotechnology \u201cL. Spallanzani\u201d, University of Pavia, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kruger-Genge, A., Blocki, A., Franke, R.P., and Jung, F. (2019). Vascular Endothelial Cell Biology: An Update. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184411"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bkaily, G., and Jacques, D. (2023). Morphological and Functional Remodeling of Vascular Endothelium in Cardiovascular Diseases. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24031998"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"166","DOI":"10.5115\/acb.22.190","article-title":"Tree of life: Endothelial cell in norm and disease, the good guy is a partner in crime!","volume":"56","author":"Marzoog","year":"2023","journal-title":"Anat. 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