Knockout of Density-Enhanced Phosphatase-1 Impairs Cerebrovascular Reserve Capacity in an Arteriogenesis Model in Mice

Abstract

Collateral growth, arteriogenesis, represents a proliferative mechanism involving endothelial cells, smooth muscle cells, and monocytes/macrophages. Here we investigated the role of Density-Enhanced Phosphatase-1 (DEP-1) in arteriogenesis in vivo, a protein-tyrosine-phosphatase that has controversially been discussed with regard to vascular cell biology. Wild-type C57BL/6 mice subjected to permanent left common carotid artery occlusion (CCAO) developed a significant diameter increase in distinct arteries of the circle of Willis, especially in the anterior cerebral artery. Analyzing the impact of loss of DEP-1 function, induction of collateralization was quantified after CCAO and hindlimb femoral artery ligation comparing wild-type and DEP-1−/− mice. Both cerebral collateralization assessed by latex perfusion and peripheral vessel growth in the femoral artery determined by microsphere perfusion and micro-CT analysis were not altered in DEP-1−/− compared to wild-type mice. Cerebrovascular reserve capacity, however, was significantly impaired in DEP-1−/− mice. Cerebrovascular transcriptional analysis of proarteriogenic growth factors and receptors showed specifically reduced transcripts of PDGF-B. SiRNA knockdown of DEP-1 in endothelial cells in vitro also resulted in significant PDGF-B downregulation, providing further evidence for DEP-1 in PDGF-B gene regulation. In summary, our data support the notion of DEP-1 as positive functional regulator in vascular cerebral arteriogenesis, involving differential PDGF-B gene expression.

Regulation of Endothelial Adherens Junctions by Tyrosine Phosphorylation

“…Paradoxically, mice completely lacking Dep1 were viable and fertile [ 209 ], suggesting that the phenotype of knock-in expressing Dep1 mutant may be due to a dominant function of this construct. However, Dep1 knockout mice, while viable, displayed deficient cerebral arteriogenesis in a model of left common carotid artery occlusion [ 210 ], thus confirming a role for wild-type Dep1 in the vasculature in vivo . A mechanism for the Dep1-mediated regulation of cell proliferation via the modulation of VEGFR2 signaling was proposed by Lampugnani et al [ 60 ].…”

Modulation of VEGF receptor 2 signaling by protein phosphatases

“…DEP-1 global null mice are unable to increase cerebrovascular blood flow (CBF) following permanent occlusion of the common carotid artery [71]. The same study did not detect differences in blood flow recovery and collateral vessel formation after seven days in a hind limb ischemia model.…”

Growth Factor Deregulation and Emerging Role of Phosphatases in Diabetic Peripheral Artery Disease

“…Although molecular mechanisms of DEP-1 are well-establish in vitro , little is known about its role in ischemia-induced hindlimb angiogenesis in PAD. Using the HLI model, a first study failed to detect variations in blood reperfusion or vessel generation in Ptprj −/− mice 7 days post-surgery ( 94 ). The deletion of DEP-1 reduced limb reperfusion and capillary density in HLI mice 14 days post-surgery compared to controls, which correlated with a loss of mobility and an increased amount of necrotic fingers ( 95 ).…”