Blood vessels, like roads, connect all parts of our body to the heart. Through those well enclosed walls, blood circulates to every crevice to deliver oxygen and nutrients vital for survival of tissues. The heart pumps blood into the aorta that branches out into arteries that in turn further branch into capillaries, together fulfilling the task of keeping the tissues and organs well nourished. But what would happen if these blood vessels got damaged or blocked? The oxygen and nutrient supply would get hindered and tissues may start dying of starvation. This inadequate blood supply- Ischemia- can lead to necrosis, gangrene, and regional paralysis.
“Ischemic heart diseases” may ring a bell since they are currently a major cause of death worldwide. They may be caused when the arteries of the heart do not receive enough blood, leading to deterioration of heart tissue and subsequent death. Ischemic strokes can also happen when blood supply to the brain is affected. Excess of cholesterol build-up in arterial walls constricts the blood flow and causes Atherosclerosis, the most common culprit for strokes. Ischemia is not confined to the heart and brain but can also happen in almost every part of the body due to variety of reasons, traumatic injury being one of them.
Immediately after injury to a blood vessel, a repair mechanism initiates to produce new vessels, increase blood flow, and quickly restore normalcy to avoid tissue damage due to lack of blood. The vessels release various proteins at the site to initiate this repair and recruit immune cells. One of the recruited immune cells, macrophages, aim to remove dead cells and contribute to maintenance of homeostasis. Today, we know that macrophages (tissue resident macrophages) are present almost in every tissue of our body, where they have been seeded since before birth and have highly variable characteristics depending on their microenvironment.
In research conducted at Uppsala University, Sweden, Vågesjö et al reveal for the first time that macrophages help in regulating blood flow after ischemic injury. They started with measuring the macrophage count and found a significant increase in ischemic muscles as compared to healthy muscle which were usually devoid of macrophages. Both, tissue resident and monocyte derived macrophages contributed to these increased numbers. They were present in regions around arteries called perivascular spaces, especially at branching points of the arteries.
On a closer look, these macrophages manifested a mix of inflammatory and anti-inflammatory phenotype. Importantly, these macrophages expressed an enzyme called inducible nitric oxide synthase (iNOS) which catalyzes production of nitric oxide. NO has various immune defense and homeostatic functions. Normally, NO released from endothelial NOS (eNOS) regulates the blood flow by vasodilating vessels. In injured vessels this is largely impaired. The eNOS expression in ischemic muscles was found to be reduced by ~85% and contrastingly iNOS expression increased by almost 3-fold. This pointed that iNOS act as a substitute source of NO in absence of eNOS. When the researchers deleted the iNOS gene in macrophages the blood flow regulation was severely affected, worsening the tissue damage. Hence, these data provided functional insights into how iNOS+ macrophages rescue tissues from ischemia.
Next, the researchers wondered how these macrophages were present at the site of blood vessel injury in the first place? The receptors for chemokines like CCR2 and CXCL12, which are released by the injured tissue, were upregulated in the iNOS expressing macrophages. To understand the significance of this increase in chemokines expression, plasmids coding for these two chemokines were injected locally and it was found that CXCL12 not only increased the number of perivascular macrophages, but also induced higher iNOS production. Follow up experiments determined that CXCL12 was indeed influencing the macrophages to produce more iNOS which in turn largely improved ischemic healing.
Through this study we now know that macrophages regulate the blood flow in ischemic tissues and are thus involved in protecting tissues from dying. Additionally, we also learn that in mice models by local overexpression of chemokine CXCL12, macrophage mediated improvement in healing was observed. Similar chemokine therapies have been attempted before against ischemic heart disease in clinical trials, but they haven’t been successful yet due to issues in delivery and dosage of the administered drug. With this novel role of macrophages discovered, more mechanistic studies could reveal newer targets and subsequently contribute to more translatable therapies.
Source: Vågesjö E, Parv K, Ahl D, Seignez C, Herrera Hidalgo C, Giraud A, Leite C, Korsgren O, Wallén H, Juusola G, Hakovirta HH, Rundqvist H, Essand M, Holm L, Johnson RS, Thålin C, Korpisalo P, Christoffersson G, Phillipson M. Perivascular Macrophages Regulate Blood Flow Following Tissue Damage. Circ Res. 2021 May 28;128(11):1694-1707. doi: 10.1161/CIRCRESAHA.120.318380.
Article author: Kevin Merchant. Kevin is a MS student at LMU Munich, Germany, who is passionate about Immunology and writing. He aims to simplify latest research so that it becomes accessible to all.
Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.
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