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Midwestern Regional Meeting, April 20–21, 2017, Chicago, IL
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Cardiology/Cardiovascular Disease

A-8: PROTEIN KINASE D1-CD36 SIGNALING AXIS PROMOTES ARTERIOLAR DIFFERENTIATION

B. Ren1

R. Ramchandran2

R. Silverstein1

1Medicine/blood Research Institute, Medical College of Wisconsin, United States of America

2Pediatrics, Obstetrics and Gynecology, Medical College of Wisconsin, United States of America

Underline denotes presenting author.

Endothelial cell (EC) heterogeneity is critical to vascular endothelial differentiation and cardiovascular disorders. Endothelial differentiation into arterial, venous or capillary (microvascular) EC phenotypes in specific tissue microenvironment will determine whether to form arteries (arteriogenesis), veins (venogenesis), or capillaries (angiogenesis). Adult ECs demonstrate differentiation plasticity (Opansky et al. 2016, Circulation; Ren et al. 2016, ATVB). Capillary EC differentiation into arterial ECs may facilitate the development of arterioles and be essential for recovering blood supply under ischemic conditions (Ren et al. 2016, ATVB; Ren et al., Circulation 2016). We observed that MAPK/Erk1/2, a downstream signaling of protein kinase D1 (PKD-1) pathway, played a key role in the arterial cell differentiation and promoted arteriogenesis under ischemia conditions (Ren, et al., 2010, JCI). In microvascular ECs (MVECs), a lipid signaling mediator (lysophosphatidic acid)-induced PKD-1/Erk1/2 signaling was involved in transcriptional repression of angiogenic regulator CD36 gene. This CD36 downregulation facilitated transcriptional reprogramming of MVECs, which subsequently expressed arteriogenic genes, contributed to microvascular remodeling, and was implicated in the capillary arterialization (formation of small arteries from capillaries). We thus hypothesized that LPA/PKD-1-CD36 signaling axis is critical to arteriolar differentiation. To test this hypothesis, we transduced MVECs with wild-type or constitutively active PKD-1 by lentiviral infection. Using real time quantitative RT-PCR, we observed that forced PKD-1 expression significantly promoted the expression of mRNA proarteriogenic genes including ephrinB2 and DLL4. The mRNA levels of Hey1, a transcription factor involved in arterial differentiation, also increased over 10 fold more than in the control. Treatment of MVECs overexpressed PKD-1 with a selective PKD inhibitor abolished PKD-1-induced arteriogenic expression. Prolonged EC …

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