Non–Endoplasmic Reticulum–Based Calr (Calreticulin) Can Coordinate Heterocellular Calcium Signaling and Vascular Function

Abstract

Our data suggest that Calr specifically at HIEL may act in a non-ER dependent manner to regulate arteriolar heterocellular communication and blood pressure.

Endothelium-Derived Hyperpolarizing Factor and Myoendothelial Coupling: The in vivo Perspective

“…Interestingly, connexins at the myoendothelial junctions are subject to functional regulation (Straub et al, 2010;Westcott and Segal, 2013), which may provide an explanation for the discrepant in vivo findings. Although significant charge transfer through MEGJ was not convincingly demonstrated in vivo, significant contributions of myoendothelial coupling to vascular function may well be of importance, for example the transfer of intracellular messengers (Looft-Wilson et al, 2017;Biwer et al, 2018;Wei et al, 2018;Wilson et al, 2019;Pohl, 2020).…”

“…If such molecules are able to diffuse through GJ it opens the possibility that non-electrotonic mechanisms contribute to vascular tone regulation, e.g., diffusion of IP 3 and/or Ca 2+ ions in either direction ( Isakson et al, 2007 ; Isakson, 2008 ). For example, the transfer of Ca 2+ from activated smooth muscle to endothelium has been implicated in a feedback mechanism that evokes an endothelial dilation, thereby counterbalancing the constriction initiated in the smooth muscle by e.g., phenylephrine ( Dora et al, 1997 ; Yashiro and Duling, 2000 ; Kerr et al, 2012 ; Biwer et al, 2018 ; Wei et al, 2018 ; Wilson et al, 2019 ). This feedback is tightly controlled ( Straub et al, 2012 ; Biwer et al, 2018 ) and, interestingly, the artificial modulation of heterocellular contact in larger arteries may alter their vascular function ( Shu et al, 2019 ).…”

“…For example, the transfer of Ca 2+ from activated smooth muscle to endothelium has been implicated in a feedback mechanism that evokes an endothelial dilation, thereby counterbalancing the constriction initiated in the smooth muscle by e.g., phenylephrine ( Dora et al, 1997 ; Yashiro and Duling, 2000 ; Kerr et al, 2012 ; Biwer et al, 2018 ; Wei et al, 2018 ; Wilson et al, 2019 ). This feedback is tightly controlled ( Straub et al, 2012 ; Biwer et al, 2018 ) and, interestingly, the artificial modulation of heterocellular contact in larger arteries may alter their vascular function ( Shu et al, 2019 ). The hypothesis that myoendothelial junctions serve as conduits for charge transfer and represent mechanistically the EDH-type dilation instead of an EDHF that traverses the extracellular space has been reviewed excellently in more detail elsewhere ( Griffith, 2004 ; Figueroa and Duling, 2009 ; de Wit and Griffith, 2010 ; Garland et al, 2011 ; Ellinsworth et al, 2014 ; Freed and Gutterman, 2017 ; Garland and Dora, 2017 ).…”

“…We describe in this short review the structural requirements and illuminate the experimental evidence obtained in vivo that argues against or in favor of the hypothesis that EDHF indeed is an EDH-type dilation rather than being a freely diffusible molecule. Other important functions of myoendothelial coupling, including the transfer of calcium or intracellular messengers, such as inositol-1,4,5-triphosphate (IP3) that modulate vascular responses (Looft-Wilson et al, 2017;Biwer et al, 2018; FIGURE 1 | A multitude of endothelial molecules and mechanisms (depicted in yellow boxes) relax vascular smooth muscle. The well-accepted chemical mediators such as nitric oxide (NO) and prostaglandins (PG) are shown, and a variety of substances that have been suggested to underly the endothelium-dependent hyperpolarization (EDH)-type dilation.…”

“…We describe in this short review the structural requirements and illuminate the experimental evidence obtained in vivo that argues against or in favor of the hypothesis that EDHF indeed is an EDH-type dilation rather than being a freely diffusible molecule. Other important functions of myoendothelial coupling, including the transfer of calcium or intracellular messengers, such as inositol-1,4,5-triphosphate (IP3) that modulate vascular responses ( Looft-Wilson et al, 2017 ; Biwer et al, 2018 ; Wei et al, 2018 ; Wilson et al, 2019 ) are reviewed in detail elsewhere ( Billaud et al, 2014 ; Straub et al, 2014 ; Pogoda and Kameritsch, 2019 ; Pohl, 2020 ) and are not addressed in detail in this manuscript. This aspect is mainly examined in vitro and due to the lack of experimental data, it is currently unknown if such a signaling pathway is of importance in vivo .…”