*Article* **Isoform-Specific Roles of ERK1 and ERK2 in Arteriogenesis**

#### **Nicolas Ricard 1, Jiasheng Zhang 1, Zhen W. Zhuang 1 and Michael Simons 1,2,\***


Received: 5 November 2019; Accepted: 18 December 2019; Published: 21 December 2019

**Abstract:** Despite the clinical importance of arteriogenesis, this biological process is poorly understood. ERK1 and ERK2 are key components of a major intracellular signaling pathway activated by vascular endothelial growth (VEGF) and FGF2, growth factors critical to arteriogenesis. To investigate the specific role of each ERK isoform in arteriogenesis, we used mice with a global *Erk1* knockout as well as *Erk1* and *Erk2* floxed mice to delete *Erk1* or *Erk2* in endothelial cells, macrophages, and smooth muscle cells. We found that ERK1 controls macrophage infiltration following an ischemic event. Loss of ERK1 in endothelial cells and macrophages induced an excessive macrophage infiltration leading to an increased but poorly functional arteriogenesis. Loss of ERK2 in endothelial cells leads to a decreased arteriogenesis due to decreased endothelial cell proliferation and a reduced eNOS expression. These findings show for the first time that isoform-specific roles of ERK1 and ERK2 in the control of arteriogenesis.

**Keywords:** angiogenesis; arteriogenesis; ERK; VEGF; endothelial cells; inflammation; macrophages
