Premium
Shear‐stress sensitive endothelial K channels play major role in flow‐induced vasodilation
Author(s) -
Ahn Sang Joon,
Fancher Ibra S,
Bian Jingtan,
Zhang Chong Xu,
Gaffin Robert,
Phillips Shane A,
Levitan Irena
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1007.24
Subject(s) - vasodilation , mesenteric arteries , enos , endothelial dysfunction , medicine , endocrinology , endothelial stem cell , shear stress , chemistry , in vitro , artery , materials science , nitric oxide , biochemistry , nitric oxide synthase , composite material
Inwardly rectifying K + (Kir) channels are known to be a putative flow sensor of endothelial cells but their role in the sensitivity of vascular endothelial cells to flow has not been established. In this study, we demonstrate that genetic deficiency of Kir2.1 results in significant loss of flow‐induced activation of the AKT/eNOS cascade, flow‐induced NO release and flow‐induced vasodilation in murine mesenteric arteries. First, we established the primary endothelial cells isolated from murine mesenteric arteries and showed their expression of functional Kir2.1 channels sensitive to shear stress. In order to determine the role of Kir2.1 in flow‐induced endothelial signaling and vasodilaton, we used two approaches: i) a genetic deficiency model, Kir2.1 heterozygous mouse model, a genetically Kir2.1 deficient mouse and ii) i) Ba2+, a well‐known Kir blocker. We observed that, as expected, the Kir2.1 expression level and the flow‐induced whole‐cell currents significantly lower in the endothelial cells from Kir2.1+/− mouse as compared to WT. Furthermore, flow‐induced vasodilation was significantly reduced in Kir2.1+/− mesenteric arteries as compared to WT controls. Exposure of WT arteries to Ba2+ ahad the same effect arteries (92.8±3.2% vs 48±5.6% vs 42.2±2.3%, WT vs WT with Ba2+ vs Kir2.1+/−). Kir2.1 deficiency also resulted in the loss of flow‐induced activation of eNOS and Akt, as well as reduction of NO generation. Notably, EC‐specific over‐expression of Kir2.1 resulted in full rescue of all the flow‐induced functions described above: AKT/eNOS activation, NO release and vasodilation. We also observed that Kir‐independent component of FIV was abrogated by blocking Ca 2+ ‐sensitive K + channels. Kir2.1 regulation on endothelium‐independent and K + ‐induced vasodilation was gone in denuded arteries. Kir2.1 +/− mice also showed higher mean blood pressure measured by carotid artery cannulation and increased microvascular resistance measured using a volume‐pressure recording tail cuff. More importantly, blocking of Kir channels also significantly decreased flow‐induced vasodilation in human subcutaneous adipose microvessels. Taken together, our observations suggest that endothelial Kir contribute to flow‐induced vasodilation of mouse mesenteric arteries through NO‐dependent mechanism, whereas Ca 2+ ‐sensitive K + channels mediate FIV with NO‐independent pathway. Kir2 channels also regulate blood pressure and vascular resistance. Finally, we also show that Kir channels also regulate FIV in human sub‐cutaneous microvessels. Support or Funding Information NIH grants HL‐073965 and HL083298 to Irena Levitan NIH grants T32 DK080674 to Ibra Fancher