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Abstract
Endothelial nitric oxide synthase (eNOS)-related vessel relaxation is a highly coordinated process that regulates blood flow and pressure and is dependent on caveolae. Here, we investigated the role of caveolar plasma membrane stabilization by the dynamin-related ATPase EHD2 on eNOS-nitric oxide (NO)-dependent vessel relaxation. Loss of EHD2 in small arteries led to increased numbers of caveolae that were detached from the plasma membrane. Concomitantly, impaired relaxation of mesenteric arteries and reduced running wheel activity were observed in EHD2 knockout mice. EHD2 deletion or knockdown led to decreased production of nitric oxide (NO) although eNOS expression levels were not changed. Super-resolution imaging revealed that eNOS was redistributed from the plasma membrane to internalized detached caveolae in EHD2-lacking tissue or cells. Following an ATP stimulus, reduced cytosolic Ca2+ peaks were recorded in human umbilical vein endothelial cells (HUVECs) lacking EHD2. Our data suggest that EHD2-controlled caveolar dynamics orchestrates the activity and regulation of eNOS/NO and Ca2+ channel localization at the plasma membrane.
Highlights
Caveolae are small plasma membrane invaginations of 80 nm in size
We previously described that adipocytes and fibroblasts in the Eps15 homology domain containing protein 2 (EHD2) knockout mouse model contain an increased number of caveolae that are detached from the plasma membrane [33]
In the complete absence of caveolae due to Cav1 deletion, increased Endothelial nitric oxide synthase (eNOS) activity was observed [60]. These results indicate that increased eNOS internalization due to caveolae internalization in EHD2 del/del cells mechanistically differs from eNOS translocation to the cytosol upon a physiological stimulus
Summary
Caveolae are small plasma membrane invaginations of 80 nm in size. They are most abundantly found in adipocytes and endothelial cells in which they compensate for mechanical membrane tension [1,2,3,4]. Caveolae are involved in endocytic processes like cellular lipid uptake [5,6,7,8] or cholera toxin internalization [9,10,11]. Caveolin (Cav1) negatively regulates the activity of endothelial nitric oxide synthase (eNOS) [12,13,14].
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