Possible new venues for the treatment of ischemic disorders

26 September 2013

​Occlusion of the main arterial route redirects blood flow to the collateral circulation. Max Mazzone, VIB Vesalius Research Center, KU Leuven, investigates the genetic and molecular
mechanisms that are responsible for reestablishing the blood flow. Using a mouse model of hind limb ischemia, two members of Max’ team, Alexander Hamm and Lorenzo Veschini, were able to demonstrate that TIE2 induction in macrophages is required to promote the latter’s proarteriogenic functions. These findings suggest possible new venues for the treatment of ischemic disorders.

Previously you reported that macrophages that were genetically modified to express low levels of PHD2 displayed an arteriogenic phenotype. What additional discovery have you made now?
Max: In this study we show that the switch in macrophage phenotype is the result of angiopoietin-1
(ANG1)-mediated PHD2 repression, independent of low oxygen tension (hypoxia) – a condition that
characterizes the lower ischemic limb but is not present in the higher limb. ANG1-dependent PHD2
repression initiates a feed-forward loop mediated by the induction of ANG receptor TIE2 in macrophages. Using gene silencing and cell depletion strategies, we were able to demonstrate that TIE2 induction in macrophages is required to promote the proarteriogenic functions that enable the formation of collateral vessels, which branch in the higher limb following arterial obstruction. These collateral vessels allow the blood flow to bypass the occlusion point, saving the tissue from ischemic necrosis. The project required international collaboration with colleagues in Portugal, Switzerland, Italy, Spain and Finland.

What did they contribute?
Just like several others in my group, this project relies on a number of cutting-edge tools and
technologies that require the resources only a network of expert scientists can provide, including
pivotal reagents such as lentiviral vectors and technical know-how. In order to maximize our
group’s benefit from these contacts, we avoided outsourcing the central experiments and instead
set up in-house training for our group members by various international colleagues with the right
expertise. This means that, instead of having a onetime impact, this collaboration will continue to bear fruit.

What are the likely implications of these findings?
Alexander: By better understanding the main regulators of collateral vessel formation, we can pave the way for successful therapies for ischemia, thus far not available. In particular, cell-based therapies using TIE2-expressing and/ or PHD2 hypomorphic macrophages might be a promising alternative to short-lived pharmacological compounds. A proof-of-concept has been shown by
Patel et al. in the same issue of EMBO Mol Med. Whether these will be heterologous or autologous
depends on the concomitant development of gene manipulation tools such as lentiviral or adenoassociated vectors.

Hamm and Veschini et al.
EMBO Mol Med, 2013

(c) Max Mazzone & Alexander Hamm