Functional Role of STIM-1 and Orai1 in Human Microvascular Aging

Cells. 2022 Nov 18;11(22):3675. doi: 10.3390/cells11223675.

Abstract

The impact of aging on vascular function is heterogeneous depending on the vascular territories. Calcium regulation plays a key role in vascular function and has been implicated in aging-related hypercontractility of corpus cavernosum. We aimed to evaluate stromal interaction molecule (STIM)/Orai system involvement in aging-related vascular alterations in the human macro and microvasculature. Aortae specimens and mesenteric arteries (MA), obtained from 45 organ donors, were functionally evaluated in organ chambers and wire myographs. Subjects were divided into groups either younger or older than 65-years old. The expressions of STIM-1, Orai1, and Orai3 were determined by immunofluorescence in the aorta and MA, and by Western blot in the aorta homogenates. The inhibition of STIM/Orai with YM-58483 (20 μM) reversed adrenergic hypercontractility in MA from older subjects but did not modify aging-related hypercontractility in the aortic strips. Aging was related to an increased expression of Orai1 in human aorta, while Orai1 and STIM-1 were upregulated in MA. STIM-1 and Orai1 protein expressions were inversely correlated to endothelial function in MA. Circulating levels of Orai1 were correlated with the inflammatory factor TNF-α and with the endothelial dysfunction marker asymmetric dimethylarginine. Aging is associated with an increased expression of the STIM/Orai system in human vessels with functional relevance only in the microvascular territory, suggesting its role in aging-related microvascular dysfunction.

Keywords: Orai channel; STIM-1; aging; human mesenteric arteries; vascular function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aging
  • Calcium / metabolism
  • Calcium Channels* / metabolism
  • Calcium Signaling* / physiology
  • Humans
  • Middle Aged
  • ORAI1 Protein / metabolism

Substances

  • Calcium
  • Calcium Channels
  • ORAI1 Protein
  • ORAI1 protein, human
  • STIM1 protein, human

Grant support

The present work was funded by grants from the Spanish Ministry of Economy, Industry, and Competitiveness, and was cofinanced by the European Regional Development Funds (Instituto de Salud Carlos III, PI15/00674; PI15/01160; PI15/01969; PI20/00977) and the Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CB16/10/00464), as well as the Fundación Francisco Soria Melguizo (project: Papel de la disfunción MITOcondrial en la relación entre multimorbilidad crónica y deterioro FUNcional en ancianos. El Proyecto MITOFUN) and the European Society for Sexual Medicine (Research Grant RG17-10).