Endothelial C-Type Natriuretic Peptide Acts on Pericytes to Regulate Microcirculatory Flow and Blood Pressure
Endothelial C-Type Natriuretic Peptide Acts on Pericytes to Regulate Microcirculatory Flow and Blood Pressure
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DOI：
10.1161/circulationaha.117.033383
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发表时间：
2018-07-31
期刊：
影响因子：
37.8
通讯作者：
Kuhn, Michaela
中科院分区：
文献类型：
--
作者：
Spiranec, Katarina;Chen, Wen;Kuhn, Michaela
背景：外周血管阻力对动脉血压水平有重要影响。血管内皮细胞C型利钠肽(CNP)参与局部血管张力调节，但靶细胞的作用仍存在争议。CGMP的鸟苷酸环化酶-B(GC-B)受体在血管平滑肌细胞(SMCs)中表达。然而，内皮细胞特异性CNP基因敲除的小鼠是高血压的，而血管SMC中GC-B缺失的小鼠血压没有改变。方法：我们分析了CNP的血管扩张反应是否沿血管树变化，即GC-B受体是否在微血管类型的细胞中表达。将携带Gc-B(Npr2)基因的小鼠与Tie2-Cre或PDGF-R-Cre(ERT2)系杂交，获得内皮细胞、毛细血管小动脉前小动脉SMC和毛细血管周细胞缺乏Gc-B的小鼠。结合活体显微镜、有创和无创血流动力学、原位细胞周cAMP水平的荧光能量转移研究和肾脏生理学，分析CNP/GC-B/cGMP信号是否以及如何调节微循环张力和血压。结果：活体显微镜研究显示，CNP对小动脉和毛细血管的血管扩张作用增强。CNP始终不能阻止内皮素-1引起的近端小动脉的急性收缩，但完全逆转了毛细血管前小动脉和毛细血管的内皮素效应。在这里，GC-B受体在内皮细胞和壁细胞中都有表达，即在周细胞中表达。值得注意的是，CNP的血管扩张作用在内皮GC-B缺失的小鼠中得以保留，但在微循环SMC和周细胞中的GC-B缺失的小鼠中消失。CNP通过GC-B/cGMP信号调节周细胞内的两个信号级联反应：它激活cGMP依赖的蛋白激酶I来磷酸化下游靶标，如细胞骨架相关的血管扩张剂激活的磷蛋白，并抑制磷酸二酯酶3A，从而提高周细胞cAMP水平。这些途径最终阻止了内皮素诱导的周细胞钙水平升高和周细胞收缩。微循环SMC和周细胞GC-B缺失的小鼠外周阻力升高，慢性动脉高压，肾功能无改变。结论：内皮型CNP对小动脉和毛细血管远端血流有调节作用。CNP诱导的微血管SMC和周细胞内的GC-B/cGMP信号对维持正常的微血管阻力和血压是必不可少的。
Background: Peripheral vascular resistance has a major impact on arterial blood pressure levels. Endothelial C-type natriuretic peptide (CNP) participates in the local regulation of vascular tone, but the target cells remain controversial. The cGMP-producing guanylyl cyclase-B (GC-B) receptor for CNP is expressed in vascular smooth muscle cells (SMCs). However, whereas endothelial cell-specific CNP knockout mice are hypertensive, mice with deletion of GC-B in vascular SMCs have unaltered blood pressure.Methods: We analyzed whether the vasodilating response to CNP changes along the vascular tree, ie, whether the GC-B receptor is expressed in microvascular types of cells. Mice with a floxed GC-B (Npr2) gene were interbred with Tie2-Cre or PDGF-R-Cre(ERT2) lines to develop mice lacking GC-B in endothelial cells or in precapillary arteriolar SMCs and capillary pericytes. Intravital microscopy, invasive and noninvasive hemodynamics, fluorescence energy transfer studies of pericyte cAMP levels in situ, and renal physiology were combined to dissect whether and how CNP/GC-B/cGMP signaling modulates microcirculatory tone and blood pressure.Results: Intravital microscopy studies revealed that the vasodilatatory effect of CNP increases toward small-diameter arterioles and capillaries. CNP consistently did not prevent endothelin-1-induced acute constrictions of proximal arterioles, but fully reversed endothelin effects in precapillary arterioles and capillaries. Here, the GC-B receptor is expressed both in endothelial and mural cells, ie, in pericytes. It is notable that the vasodilatatory effects of CNP were preserved in mice with endothelial GC-B deletion, but abolished in mice lacking GC-B in microcirculatory SMCs and pericytes. CNP, via GC-B/cGMP signaling, modulates 2 signaling cascades in pericytes: it activates cGMP-dependent protein kinase I to phosphorylate downstream targets such as the cytoskeleton-associated vasodilator-activated phosphoprotein, and it inhibits phosphodiesterase 3A, thereby enhancing pericyte cAMP levels. These pathways ultimately prevent endothelin-induced increases of pericyte calcium levels and pericyte contraction. Mice with deletion of GC-B in microcirculatory SMCs and pericytes have elevated peripheral resistance and chronic arterial hypertension without a change in renal function.Conclusions: Our studies indicate that endothelial CNP regulates distal arteriolar and capillary blood flow. CNP-induced GC-B/cGMP signaling in microvascular SMCs and pericytes is essential for the maintenance of normal microvascular resistance and blood pressure.