Differential catalytic properties and vascular topography of murine nucleoside triphosphate diphosphohydrolase 1 (NTPDase1) and NTPDase2 have implications for thromboregulation
Differential catalytic properties and vascular topography of murine nucleoside triphosphate diphosphohydrolase 1 (NTPDase1) and NTPDase2 have implications for thromboregulation
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DOI：
10.1182/blood.v99.8.2801
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发表时间：
2002-04-15
期刊：
影响因子：
20.3
通讯作者：
Robson, SC
中科院分区：
文献类型：
--
作者：
Sévigny, J;Sundberg, C;Robson, SC
核苷三磷酸二磷酸水解酶（NTPDases）是最近描述的差异水解胞外核苷酸的γ和β磷酸残基的胞外核苷酸酶家族。这种酶活性的表达有可能影响血管系统内的核苷酸P2受体信号传导。我们和其他人已经证明，NTPDase 1（CD 39，78 kd）水解三磷酸核苷和二磷酸核苷，从而终止血小板对二磷酸腺苷（ADP）的聚集反应。相反，我们现在发现NTPDase 2（CD 39 L1，75 kd）是一种优先的核苷三磷酸酶，通过将三磷酸腺苷（ATP）转化为ADP（P2 Y（1）和P2 Y（12）受体的特异性激动剂）来激活血小板聚集。我们开发了鼠NTPDase 1和NTPDase 2的特异性抗体，并观察到这两种酶都存在于心脏血管系统中; NTPDase 1由内皮细胞、内皮细胞表达，在较小程度上由血管平滑肌表达，而NTPDase 2与肌化血管外膜、微血管周细胞和内皮下间隙中的其他细胞群相关。此外，NTPDase 2代表微血管周细胞的新标记物。NTPDases在血管系统中的差异表达表明核苷酸介导的信号传导的空间调节。在这种情况下，NTPDase 1应废除血小板聚集和招聘在完整的血管中的ADP转化为腺苷酸，而NTPDase 2的表达将促进血管损伤后外渗部位的血小板微血栓形成。我们的数据表明，特异性NTPDases与外T-核苷酸酶串联，不仅终止P2受体激活并触发腺苷受体，而且还可能允许优先激活对ADP敏感的P2受体的特定亚群（例如，P2 Y（1），P2 Y（3），P2 Y（12））和尿苷二磷酸（P2 Y（6））。(C)D 2002年，美国血液学会。
Nucleoside triphosphate diphosphohydrolases (NTPDases) are a recently described family of ectonucleotidases that differentially hydrolyze the gamma and beta phosphate residues of extracellular nucleotides. Expression of this enzymatic activity has the potential to influence nucleotide P2 receptor signaling within the vasculature. We and others have documented that NTPDase1 (CD39, 78 kd) hydrolyzes both triphosphonucleosides and diphosphonucleosides and thereby terminates platelet aggregation responses to adenosine diphosphate (ADP). In contrast, we now show that NTPDase2 (CD39L1, 75 kd), a preferential nucleoside triphosphatase, activates platelet aggregation by converting adenosine triphosphate (ATP) to ADP, the specific agonist of P2Y(1) and P2Y(12) receptors. We developed specific antibodies to murine NTPDase1 and NTPDase2 and observed that both enzymes are present in the cardiac vasculature; NTPDase1 is expressed by endothelium, endocardium, and to a lesser extent by vascular smooth muscle, while NTPDase2 is associated with the adventitia of muscularized vessels, microvascular pericytes, and other cell populations in the subendocardial space. Moreover, NTPDase2 represents a novel marker for microvascular pericytes. Differential expression of NTPDases in the vasculature suggests spatial regulation of nucleotide-mediated signaling. In this context, NTPDase1 should abrogate platelet aggregation and recruitment in intact vessels by the conversion of ADP to adenosine monophosphate, while NTPDase2 expression would promote platelet microthrombus formation at sites of extravasation following vessel injury. Our data suggest that specific NTPDases, in tandem with ecto-T-nucleotidase, not only terminate P2 receptor activation and trigger adenosine receptors but may also allow preferential activation of specific subsets of P2 receptors sensitive to ADP (eg, P2Y(1), P2Y(3), P2Y(12)) and uridine diphosphate (P2Y(6)). (C)D 2002 by The American Society of Hematology.