Reho John J, Zheng Xiaoxu, Benjamin James E, Fisher Steven A
Am J Physiol Heart Circ Physiol. 2014 Aug 15;307(4):H563-73. doi: 10.1152/ajpheart.00250.2014.
There is evidence for developmental origins of vascular dysfunction yet little understanding of maturation of vascular smooth muscle (VSM) of regional circulations. We measured maturational changes in expression of myosin phosphatase (MP) and the broader VSM gene program in relation to mesenteric small resistance artery (SRA) function. We then tested the role of the sympathetic nervous system (SNS) in programming of SRAs and used genetically engineered mice to define the role of MP isoforms in the functional maturation of the mesenteric circulation. Maturation of rat mesenteric SRAs as measured by qPCR and immunoblotting begins after the second postnatal week and is not complete until maturity. It is characterized by induction of markers of VSM differentiation (smMHC, γ-, α-actin), CPI-17, an inhibitory subunit of MP and a key target of α-adrenergic vasoconstriction, α1-adrenergic, purinergic X1, and neuropeptide Y1 receptors of sympathetic signaling. Functional correlates include maturational increases in α-adrenergic-mediated force and calcium sensitization of force production (MP inhibition) measured in first-order mesenteric arteries ex vivo. The MP regulatory subunit Mypt1 E24+/LZ- isoform is specifically upregulated in SRAs during maturation. Conditional deletion of mouse Mypt1 E24 demonstrates that splicing of E24 causes the maturational reduction in sensitivity to cGMP-mediated vasorelaxation (MP activation). Neonatal chemical sympathectomy (6-hydroxydopamine) suppresses maturation of SRAs with minimal effect on a conduit artery. Mechanical denervation of the mature rat renal artery causes a reversion to the immature gene program. We conclude that the SNS captures control of the mesenteric circulation by programming maturation of the SRA smooth muscle.
有证据表明血管功能障碍存在发育起源，但对局部循环中血管平滑肌（VSM）的成熟了解甚少。我们测量了肌球蛋白磷酸酶（MP）表达的成熟变化以及更广泛的VSM基因程序与肠系膜小阻力动脉（SRA）功能的关系。然后，我们测试了交感神经系统（SNS）在SRA编程中的作用，并使用基因工程小鼠来确定MP同工型在肠系膜循环功能成熟中的作用。通过qPCR和免疫印迹测量，大鼠肠系膜SRA的成熟在出生后第二周开始，直到成熟才完成。其特征是诱导VSM分化标志物（smMHC、γ-、α-肌动蛋白）、CPI-17（MP的抑制亚基和α-肾上腺素能血管收缩的关键靶点）、交感信号的α1-肾上腺素能、嘌呤能X1和神经肽Y1受体。功能相关性包括离体一级肠系膜动脉中α-肾上腺素能介导的力量成熟增加以及力量产生的钙敏化（MP抑制）。MP调节亚基Mypt1 E24+/LZ-同工型在成熟过程中在SRA中特异性上调。小鼠Mypt1 E24的条件性缺失表明E24的剪接导致对cGMP介导的血管舒张（MP激活）的敏感性成熟降低。新生儿化学交感神经切除术（6-羟基多巴胺）抑制SRA的成熟，对传导动脉的影响最小。成熟大鼠肾动脉的机械去神经支配导致向未成熟基因程序的逆转。我们得出结论，SNS通过对SRA平滑肌成熟进行编程来控制肠系膜循环。
