FRNK overexpression limits the depth and frequency of vascular smooth muscle cell invasion in a three-dimensional fibrin matrix.
FRNK overexpression limits the depth and frequency of vascular smooth muscle cell invasion in a three-dimensional fibrin matrix.
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FRNK的过表达限制了三维纤维蛋白基质中血管平滑肌细胞浸润的深度和频率。
DOI：
10.1002/jcp.22239
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发表时间：
2010-11
影响因子：
5.6
通讯作者：
Greisler, H. P.
中科院分区：
文献类型：
--
作者：
Brewster, L. P.;Ucuzian, A. A.;Brey, E. M.;Liwanag, M.;Samarel, A. M.;Greisler, H. P.
血管介入术（如血管成形术或旁路手术）后的病理性血管平滑肌细胞（VSMC）行为在血管介质的3-D环境中启动。VSMC在此处增殖，侵入周围基质，向腔迁移，并存款大量基质，导致肌内膜增生和减少的血流到关键器官和组织。由于黏着斑激酶（FAK）介导了许多VSMC对这些病理事件的反应，它提供了一个合理的药理学靶点，以限制这种侵袭性VSMC行为，并更好地了解这种疾病的细胞病理生理学。在这里，我们量化的有效性，禁用FAK在VSMCs与其显性负抑制剂，FAK相关的非激酶（FRNK），在临床相关的3-D测定。我们发现FRNK过表达降低了基质中VSMC的侵袭（长度和频率）。这些作用在存在和不存在化学有丝分裂抑制的情况下得到证实，表明FAK对细胞基质侵袭、迁移和增殖的作用利用单独和/或冗余的信号级联。从机制上讲，FAK抑制减少了其在粘着斑的定位，这导致FAK自磷酸化和丝氨酸/苏氨酸激酶AKT磷酸化的显著减少。总之，这些发现表明，FAK信号的中断可能提供一种药物工具，限制病理性VSMC细胞的行为。
Pathological vascular smooth muscle cell (VSMC) behavior after vascular interventions such as angioplasty or bypass is initiated within the 3-D environment of the vessel media. Here VSMCs proliferate, invade the surrounding matrix, migrate adluminally, and deposit substantial amounts of matrix, leading to myointimal hyperplasia and decreased blood flow to critical organs and tissue. Since focal adhesion kinase (FAK) mediates many of the VSMC responses to these pathologic events, it provides a reasonable pharmacologic target to limit this invasive VSMC behavior and to better understand the cellular pathophysiology of this disease. Here we quantified the effectiveness of disabling FAK in VSMCs with its dominant-negative inhibitor, FAK related nonkinase (FRNK), in a clinically relevant 3-D assay. We found that FRNK overexpression decreased VSMC invasion (both the length and frequency) in this matrix. These effects were demonstrated in the presence and absence of chemical mitotic inhibition, suggesting that FAK's effect on cellular matrix invasion, migration, and proliferation utilize separate and/or redundant signaling cascades. Mechanistically, FAK inhibition decreased its localization to focal adhesions which led to a significant decrease in FAK autophosphorylation and the phosphorylation of the serine/threonine kinase, AKT. Together these findings suggest that disruption of FAK signaling may provide a pharmaceutical tool that limits pathological VSMC cell behavior.
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影响因子：
7.8
作者：
Carragher, N O;Levkau, B;Ross, R;Raines, E W
通讯作者：
Raines, E W
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Yamada, KM
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作者：
Avraham, HK;Lee, TH;Avraham, S
通讯作者：
Avraham, S
影响因子：
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作者：
Heidkamp, MC;Bayer, AL;Samarel, AM
通讯作者：
Samarel, AM
影响因子：
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作者：
Hauck, CR;Hsia, DA;Schlaepfer, DD
通讯作者：
Schlaepfer, DD