Unknown,Transcriptomics,Genomics,Proteomics

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Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development

ABSTRACT: Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. Collaterals are artery-to-artery or arteriole-to-arteriole interconnections that can bypass an occlusion by providing an alternative route for blood flow to the affected tissue. The increased flow and sheer stress initiate processes that result in the remodeling (arteriogenesis) of these vessels into efficient conductance arteries. Here we report that the mixed-lineage kinase (MLK) pathway activates cJun NH2-terminal kinase (JNK) in endothelial cells. Disruption of Mlk2/3 or Jnk1/2 genes caused severe blockade of blood flow and failure to recover in the femoral artery ligation model of hindlimb ischemia because of abnormal collateral arteries. We show that the MLK-JNK pathway is essential for patterning and maturation of collateral arteries during development, but this pathway is not required for angiogenesis or arteriogenesis in adults. JNK in endothelial cells promotes Delta-like 4-induced Notch signaling and suppresses excessive sprouting angiogenesis during development. This function of the MLK-JNK pathway contributes to normal formation of native collateral arteries. The MLK-JNK pathway is therefore a key regulatory mechanism for vascular development. These data highlight the crucial importance of the collateral circulation in the response to arterial occlusive diseases. RNA-seq analysis of mouse lung endothelial cells (MLEC) of the following genotypes Cdh5-Cre+ Jnk1+/+ Jnk2+/+ Jnk3-/-(ECtrl), Cdh5-Cre- Jnk1LoxP/LoxP Jnk2LoxP/LoxP Jnk3-/- (EfCtrl), and Cdh5-Cre+ Jnk1LoxP/LoxP Jnk2LoxP/LoxP Jnk3-/- (E3KO). Three separate samples from mouse lung endothelial cells of each genotype were analyzed.

ORGANISM(S): Mus musculus

SUBMITTER: Kasmir Ramo

PROVIDER: E-GEOD-71159 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development.

Ramo Kasmir K Sugamura Koichi K Craige Siobhan S Keaney John F JF Davis Roger J RJ

eLife 20160809

Arterial occlusive diseases are major causes of morbidity and mortality. Blood flow to the affected tissue must be restored quickly if viability and function are to be preserved. We report that disruption of the mixed-lineage protein kinase (MLK) - cJun NH2-terminal kinase (JNK) signaling pathway in endothelial cells causes severe blockade of blood flow and failure to recover in the murine femoral artery ligation model of hindlimb ischemia. We show that the MLK-JNK pathway is required for the fo ...[more]

PMID: 27504807

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Project description:Background: The vascular wall of small arteries is heavily affected by high blood pressure. However, the underlying mechanisms causing vascular changes are not fully elucidated. Using a novel data-independent acquisition mass spectrometry (DIA-MS) approach, we aimed to determine the proteomic changes in small mesenteric arteries during early-onset high blood pressure in a rat model of hypertension. Methods: Snap frozen small mesenteric and renal arteries from the spontaneous hypertension rat (SHR) model and Wistar Kyoto (WKY) control rats were collected from two time points (6- and 12-weels of age) and analyzed by a label free quantitative DIA-MS workflow. Mesenteric arteries from Wister Hannover rats were included as an additional control to clarify genetic drift caused by selective inbreeding. Results: We identified a total of 3956 consistent proteins in the mesenteric artery wall and found that 286 proteins were significantly regulated in 12-weeks old SHRs compared to WKY controls. Comparing to an in silico matrisome database, we identified 38 extracellular matrix-associated proteins that could distinguish SHRs from WKY controls. Furthermore, when comparing the significantly regulated proteins identified in mesenteric and renal arteries, we identified 18 proteins, including Serpina3l, Igg-2a, ENSRNOG00000049829, Acyp2, Enpp3, Lss, Acaa1a, Basp1, an isoform of Basp1, Flot1, Flot2, Gstt1, Nit1, Ppid, Ikbkap, Poglut3, P4ha2 and Usp15, that were changed in both vascular beds. These proteins were associated with vital cellular processes, such as dyslipidemia, protease inhibition, remodeling and generation of reactive oxygen species. Majority of the identified proteins and pathways were associated with hypertension, and mapping the underlying changes help understanding the pathological processes occurring in the arterial wall during early-onset hypertension. Conclusions: Our data provides an in-depth analysis of the proteomic architecture of the mesenteric and renal artery wall from SHRs and WKY control rats. We identified 18 novel candidate proteins that highlights critical changes in small arteries of the SHR.

Dataset Information

Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development

Publications

Suppression of ischemia in arterial occlusive disease by JNK-promoted native collateral artery development.

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