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LPA/PKD-1-FoxO1 Signaling Axis Mediates Endothelial Cell CD36 Transcriptional Repression and Proangiogenic and
Bin Ren1, Brad Best1, Devi Prasadh Ramakrishnan1
1From the Department of Medicine, Medical College of Wisconsin, Milwaukee (B.R., R.L.S.); Blood Research Institute, Blood Center of Wisconsin, Milwaukee (B.R., B.B., D.P.R., R.L.S.); Department of Neurological Surgery, Cardiovascular Research Center, Massachusetts General Hospital & Harvard Medical School, Boston (B.P.W.); and Department of Cancer Biology, Mayo Clinic, Jacksonville, FL (P.S.).
Insights
Lysophosphatidic acid signaling suppresses CD36, promoting angiogenesis and vascular remodeling. This pathway involves protein kinase D1 (PKD-1) and reprogramming endothelial cells, offering therapeutic targets for cardiovascular disease and cancer.
Area of Science:
- Molecular Biology
- Cell Biology
- Vascular Biology
Background:
- CD36 receptor plays a role in atherothrombotic diseases, diabetes, cancer, and obesity.
- Lysophosphatidic acid (LPA) signaling downregulates CD36 transcription via protein kinase D1 (PKD-1).
Purpose of the Study:
- To elucidate the mechanisms of LPA-mediated regulation of CD36 transcription and endothelial cell function.
- To understand the role of nuclear transcriptional complexes in this process.
Main Methods:
- Utilized microvascular endothelial cells for studying angiogenesis and CD36 transcription.
- Employed gene transfection, RT-qPCR, DNA-binding assays, chromatin immunoprecipitation, co-immunoprecipitation, and microscopy.
- Performed spheroid-based and in vivo Matrigel angiogenesis assays, and a mouse tumor angiogenesis model.
Main Results:
- LPA-mediated CD36 repression involves PKD-1 signaling and the formation of a forkhead box protein O1-histone deacetylase 7 complex in the nucleus.
- CD36 transcriptional suppression led to endothelial cell reprogramming, expressing ephrin B2, a marker for angiogenesis and arteriogenesis.
- PKD-1 signaling was crucial for angiogenic branching morphogenesis and in vivo angiogenesis, as evidenced in a Lewis Lung Carcinoma model.
Conclusions:
- LPA/PKD-1 signaling induces nuclear accumulation of histone deacetylase 7, which interacts with forkhead box protein O1 to suppress CD36 transcription.
- This process silences the antiangiogenic switch, leading to proangiogenic and proarteriogenic reprogramming of endothelial cells.
- Targeting this signaling cascade presents a novel therapeutic strategy for ischemic cardiovascular diseases and cancer.
Objective:
CD36 is a scavenger and antiangiogenic receptor that is important in atherothrombotic diseases, diabetes mellitus, cancer, and obesity. Lysophosphatidic acid, a phospholipid signaling mediator, abolishes endothelial cell responses to antiangiogenic proteins containing thrombospondin type 1 homology domains by downregulating endothelial CD36 transcription via protein kinase D1 (PKD-1) signaling. We aimed to understand mechanisms by which lysophosphatidic acid-mediated angiogenic signaling is integrated to regulate CD36 transcription and endothelial cell function via a nuclear transcriptional complex.
Approach And Results:
Microvascular endothelial cells expressing CD36 were used for studying angiogenic signaling and CD36 transcription. Gene transfection and transduction, RT-qPCR, avidin-biotin-conjugated DNA-binding assay, chromatin immunoprecipitation assay, co-immunoprecipitation, proximal ligation assay, and immunofluorescence microscopy showed that lysophosphatidic acid-mediated CD36 transcriptional repression involved PKD-1 signaling mediated formation of forkhead box protein O1-histone deacetylase 7 complex in the nucleus. Unexpectedly, turning off CD36 transcription initiated reprogramming microvascular endothelial cells to express ephrin B2, a critical molecular signature involved in angiogenesis and arteriogenesis. Spheroid-based angiogenesis and in vivo Matrigel angiogenesis assays indicated that angiogenic branching morphogenesis and in vivo angiogenesis were dependent on PKD-1 signaling. A mouse tumor angiogenesis model revealed enhanced PKD-1 signaling and expression of ephrin B2 and smooth muscle actin in neovessels of Lewis Lung Carcinomas, along with low-CD36 expression or CD36 deficiency.
Conclusions:
Lysophosphatidic acid/PKD-1 signaling leads to nuclear accumulation of histone deacetylase 7, where it interacts with forkhead box protein O1 to suppress endothelial CD36 transcription and mediates silencing of antiangiogenic switch, resulting in proangiogenic and proarteriogenic reprogramming. Targeting this signaling cascade could be a novel approach for ischemic cardiovascular disease and cancer.
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