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  1. B Ren1,2,
  2. RL Silverstein1,2,
  3. R Yuan2,
  4. L Dong2,3
  1. 1Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
  2. 2Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, United States
  3. 3Department of Pharmacology, Anhui Medical University, Hefei, CHINA


Recovery from thrombotic occlusion of large arteries requires neovascularization accompanied by effective arterial remodeling that stimulates collateral artery growth to provide compensatory blood flow to the downstream ischemic tissues. Endothelial cells (ECs) are a critical cellular element in this process and ischemia is associated with changes in the EC transcriptional reprogramming. Recently we showed that the lipid signaling mediator lysophosphatidic acid (LPA) reprograms microvascular EC (MVEC) gene transcription by initially silencing CD36 (an antiangiogenic receptor) and then up-regulating expression of several arteriogenic genes, including ephrin B2. LPA-mediated CD36 gene regulation was due to activation of protein kinase PKD-1 and subsequent assembly of a nuclear complex containing histone deacetylase HDAC7 and transcription factor FoxO1. We hypothesize that CD36 downregulation and arterial gene activation via PKD-1 may occur under conditions where LPA is generated, such as ischemia, and be necessary for effective de novo arteriogenesis. We thus knocked down endogenous CD36 expression or overexpressed constitutively active PKD-1 (PKD-CA) by lentiviral transducing MVECs with CD36 shRNA or PKD-CA. In both cases we observed increased expression of arterial genes including ephrinB2, the key gene in arterial morphogenesis. Furthermore, we produced a novel EC-specific PKD-1 null line by crossing Cdh5-cre with prkd1tm1Eno mice. We used immunohistochemistry to show incomplete EC coverage on vascular wall in mature blood vessels in the lung and heart in these transgenic mice. To determine whether EC PKD-1 signaling is essential for arteriogenesis in vivo, we established a murine hindlimb ischemia model and found that functional outcomes, assessed by the Tarlov ischemia scale, were significantly worse in the EC-specific PKD-1 null mice compared to controls over 21 days (3.33 vs 6). Laser Doppler imaging also demonstrated impaired blood perfusion of the limb in the null mice over 21 days [L/R ratio 0.09±0.12 vs 0.52±0.2 (control) at day 21], consistent with a defect in arteriogenesis. In conclusion, our study supports the hypothesis that PKD-1 signaling reprograms MVECs for arteriogenic gene transcription and contributes to functional revascularization in ischemic conditions, and that the transcriptional level of MVEC CD36 may play a role in this proarteriogenic process. Targeting MVEC PKD-1/CD36 signaling pathways could potentially improve tissue perfusion and benefit patients with advanced atherosclerotic vascular disease.

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