**Local Mast Cell Activation Promotes Neovascularization**

**Ilze Bot 1, Daniël van der Velden 1, Merel Bouwman 1,2,3, Mara J. Kröner 1, Johan Kuiper 1, Paul H. A. Quax 2,3 and Margreet R. de Vries 2,3,\***


Received: 18 December 2019; Accepted: 10 March 2020; Published: 12 March 2020

**Abstract:** Mast cells have been associated with arteriogenesis and collateral formation. In advanced human atherosclerotic plaques, mast cells have been shown to colocalize with plaque neovessels, and mast cells have also been associated with tumor vascularization. Based on these associations, we hypothesize that mast cells promote angiogenesis during ischemia. In human ischemic muscle tissue from patients with end-stage peripheral artery disease, we observed activated mast cells, predominantly located around capillaries. Also, in mouse ischemic muscles, mast cells were detected during the revascularization process and interestingly, mast cell activation status was enhanced up to 10 days after ischemia induction. To determine whether mast cells contribute to both arteriogenesis and angiogenesis, mast cells were locally activated immediately upon hind limb ischemia in C57Bl/6 mice. At day 9, we observed a 3-fold increase in activated mast cell numbers in the inguinal lymph nodes. This was accompanied by an increase in the amount of Ly6Chigh inflammatory monocytes. Interestingly, local mast cell activation increased blood flow through the hind limb (46% at day 9) compared to that in non-activated control mice. Histological analysis of the muscle tissue revealed that mast cell activation did not affect the number of collaterals, but increased the collateral diameter, as well as the number of CD31+ capillaries. Together, these data illustrate that locally activated mast cell contribute to arteriogenesis and angiogenesis.

**Keywords:** arteriogenesis; angiogenesis; innate immunity; mast cell
