Platelet-derived growth factor receptor beta signaling is required for efficient epicardial cell migration and development of two distinct coronary vascular smooth muscle cell populations.
Platelet-derived growth factor receptor beta signaling is required for efficient epicardial cell migration and development of two distinct coronary vascular smooth muscle cell populations.
复制标题
DOI：
10.1161/circresaha.108.176768
复制
发表时间：
2008-12-05
影响因子：
20.1
通讯作者：
Tallquist MD
中科院分区：
文献类型：
--
作者：
Mellgren AM;Smith CL;Olsen GS;Eskiocak B;Zhou B;Kazi MN;Ruiz FR;Pu WT;Tallquist MD
心外膜在冠状动脉形成和心肌发育中起着至关重要的作用，但控制该组织发育和分化的信号尚不清楚。为了研究血小板衍生生长因子受体β (PDGFRβ)在心外膜衍生血管平滑肌细胞（VSMC）发育中的作用，我们检测了PDGFRβ-/-和PDGFRβ心外膜突变心脏。我们发现PDGFRβ-/-心脏不能在心脏腹侧表面形成优势冠状血管，心肌变薄，完全缺乏冠状动脉VSMC （cVSMC）。这些缺陷与心外膜的原发缺陷一致。为了验证这些缺陷是心外膜衍生物特异性的，我们产生了心外膜PDGFRβ缺失的小鼠，导致主动脉远端cVSMC减少。cVSMC的区域性缺失表明，cVSMC可能有两个来源，心外膜和非心外膜，两者都依赖于PDGFRβ。在缺乏PDGFRβ信号的情况下，心外膜细胞采用不规则的肌动蛋白细胞骨架，导致心外膜细胞在体内异常迁移到心肌。此外，PDGF受体刺激可促进心外膜细胞迁移，pdgfr β驱动的磷酸肌苷激酶（PI3K）信号在这一过程中起关键作用。我们的数据表明，PDGFRβ是形成两种不同的cVSMC群体所必需的，PDGFRβ- pi3k信号的丢失会破坏心外膜细胞的迁移。
The epicardium plays an essential role in coronary artery formation and myocardial development, but signals controlling the development and differentiation of this tissue are not well understood. To investigate the role of platelet derived growth factor receptor β (PDGFRβ) in development of epicardial-derived vascular smooth muscle cells (VSMC), we examined PDGFRβ-/- and PDGFRβ epicardial-mutant hearts. We found that PDGFRβ-/- hearts failed to form dominant coronary vessels on the ventral heart surface, had a thinned myocardium, and completely lacked coronary VSMC (cVSMC). This constellation of defects was consistent with a primary defect in the epicardium. To verify that these defects were specific to epicardial derivatives, we generated mice with an epicardial deletion of PDGFRβ that resulted in reduced cVSMC distal to the aorta. The regional absence of cVSMC suggested that cVSMC could arise from two sources, epicardial and non-epicardial, and that both were dependent on PDGFRβ. In the absence of PDGFRβ signaling, epicardial cells adopted an irregular actin cytoskeleton leading to aberrant migration of epicardial cells into the myocardium in vivo. In addition, PDGF receptor stimulation promoted epicardial cell migration, and PDGFRβ-driven phosphoinositide 3' kinase (PI3K) signaling was critical for this process. Our data demonstrate that PDGFRβ is required for the formation of two distinct cVSMC populations and that loss of PDGFRβ-PI3K signaling disrupts epicardial cell migration.