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Commentary
Open Access | 
10.1172/JCI158280
Modulating the immune response to reduce hypertension-associated cardiovascular damage
Daniel Henrion
Angers University, MitoVasc Department, Team 2 (CarMe), Angers University Hospital (CHU of Angers), CNRS, INSERM, Angers, France.
Address correspondence to: Daniel Henrion, MITOVASC Department, IRIS-2 Building, 3 rue Roger Amsler, CS 30007, F-49055 Angers, France. Phone: 00.33.2.44.68.82.75; Email: daniel.henrion@inserm.fr.
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Published March 15, 2022 - More info
J Clin Invest. 2022;132(6):e158280. https://doi.org/10.1172/JCI158280.
© 2022 Henrion et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
The causative role of inflammation in hypertension-related cardiovascular diseases is evident and calls for development of specific immunomodulatory therapies. We tested the therapeutic efficacy and mechanisms of action of developmental endothelial locus-1 (DEL-1), an endogenous antiinflammatory factor, in angiotensin II– (ANGII–) and deoxycorticosterone acetate–salt–induced (DOCA-salt–induced) cardiovascular organ damage and hypertension. By using mice with endothelial overexpression of DEL-1 (EC-Del1 mice) and performing preventive and interventional studies by injecting recombinant DEL-1 in mice, we showed that DEL-1 improved endothelial function and abrogated aortic adventitial fibrosis, medial thickening, and loss of elastin. DEL-1 also protected the mice from cardiac concentric hypertrophy and interstitial and perivascular coronary fibrosis and improved left ventricular function and myocardial coronary perfusion. DEL-1 prevented aortic stiffness and abolished the progression of hypertension. Mechanistically, DEL-1 acted by inhibiting αvβ3 integrin–dependent activation of pro-MMP2 in mice and in human isolated aorta. Moreover, DEL-1 stabilized αvβ3 integrin–dependent CD25+FoxP3+ Treg numbers and IL-10 levels, which were associated with decreased recruitment of inflammatory cells and reduced production of proinflammatory cytokines in cardiovascular organs. The demonstrated effects and immune-modulating mechanisms of DEL-1 in abrogation of cardiovascular remodeling and progression of hypertension identify DEL-1 as a potential therapeutic factor.
Authors
Theresa Failer, Michael Amponsah-Offeh, Aleš Neuwirth, Ioannis Kourtzelis, Pallavi Subramanian, Peter Mirtschink, Mirko Peitzsch, Klaus Matschke, Sems M. Tugtekin, Tetsuhiro Kajikawa, Xiaofei Li, Anne Steglich, Florian Gembardt, Annika C. Wegner, Christian Hugo, George Hajishengallis, Triantafyllos Chavakis, Andreas Deussen, Vladimir Todorov, Irakli Kopaliani
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Modulation of the immune system
Failer et al. (8) offer a tool for the treatment of hypertension and especially the treatment of the vascular and cardiac hypertrophy associated with hypertension, cardiac failure, and death. Developmental endothelial locus-1 (DEL-1) is an endogenous antiinflammatory glycoprotein that reduces immune cell recruitment (9). Notably, DEL-1 could fill a void in the treatment of hypertension between pharmacological tools and vaccines. The authors showed that DEL-1 stopped the increase in blood pressure and normalized endothelium-dependent relaxation in two different mouse models of hypertension: one with angiotensin II infusion and one with volume overload and thus reduced renin-angiotensin activity (Figure 1). The findings suggest that DEL-1 could efficiently prevent both essential and secondary hypertension. Indeed, in hypertensive mice, both the endothelial overexpression of DEL-1 and the injection of recombinant DEL-1 suppressed aorta and heart hypertrophy and fibrosis and improved left-ventricular function and coronary perfusion. Thus, DEL-1 seems efficient against the main deleterious consequences of hypertension and offers an opportunity for the management of hypertension through modulation of the immune system.
Figure 1DEL-1 protects against hypertension-induced cardiovascular damage. Failer et al. (8) demonstrated that the immunomodulator protein DEL-1 reduced αvβ3 integrin–mediated activation of MMP2, leading to decreased inflammation in the heart and in the aorta in hypertension. This protection involved an improvement of the Treg/IL-10 balance and a reduction in immune cell infiltration. The crosstalk between macro- and microcirculation induces a vicious cycle in hypertension, whereas an efficient treatment affecting both could lead to a virtuous circle.
Whereas the study by Failer et al. (8) shows an efficient effect of DEL-1 on cardiac and aortic hypertrophy, hypertension involves a complex crosstalk between macrocirculation and microcirculation (Figure 1). As described in a recent review, “The two are tightly interconnected into a dangerous cross-link during hypertension” (3). The effect of DEL-1 on microcirculation remains to be explored, and the possible role of DEL-1 in the structure and function of resistance arteries is an important topic for future research. Indeed, these small arteries have a major role in blood pressure control and in patients with hypertension resistance arteries undergoing inward eutrophic remodeling (3). Although resistance artery remodeling excludes substantial changes in the amount of wall tissue and generally maintains the media cross-sectional area, increased oxidative stress and inflammation have been demonstrated in hypertension (10). Nevertheless, hypertrophic remodeling has been observed in resistance arteries in hypertensive people with diabetes and obesity and in several forms of secondary hypertension (11, 12). Thus, reducing inflammation using DEL-1 could also benefit small resistance artery remodeling, at least in hypertension associated with other risk factors. Additionally, the effect of DEL-1 on αvβ3 integrins implies that DEL-1 could interact with resistance artery tone and hence affect inward arterial eutrophic remodeling observed in essential hypertension. Indeed, αvβ3 integrins are involved in the myogenic constriction of resistance arteries (13). Excessive pressure-induced myogenic tone of these small arteries has a role in the development of hypertension and is a determinant of the eutrophic inward remodeling observed in essential hypertension (14–16).
DEL-1 is also efficient in promoting angiogenesis (17), an effect that could benefit hypertension-associated microvascular and capillary rarefaction (18). Thus, a treatment that increases DEL-1 activity may positively affect the microvascular rarefaction observed in hypertension, although DEL-1 had no obvious effect in peripheral arterial disease (19). DEL-1 has also been shown to inhibit postischemic revascularization in a mouse model of hind-limb ischemia (20). Thus, more investigation is needed to clarify this issue.
As DEL-1 reduces immune cell recruitment in the aorta, one can also postulate that it could be a useful tool against atherosclerosis and possibly aortic aneurysm. Indeed, chronic inflammation governs the progress of atherosclerotic lesions with a major role for adaptive immunity (21). Similarly, the inflammatory process plays a key role in abdominal aortic aneurysm with the involvement of different monocyte and macrophage subsets in the initiation and in the progression of the disease (22). Thus, future studies should focus on the role of DEL-1 in atherosclerosis and aortic aneurysm, as a modulator of the immune response with antiinflammatory properties is likely to have a therapeutic potential in these pathologies.
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