Introduction:
Hypertension is increasingly being recognized not only as a disorder of the cardiovascular system but also as a chronic low-grade inflammatory disease. Hypertension-induced inflammation within the myocardium drives progressive cardiac remodeling, thereby linking immune responses and hypertension to a vicious cycle of sustained pressure overload. Developmental Endothelial Locus-1 (DEL-1) is an endothelial glycoprotein with anti-inflammatory and pro-resolving effects by modulating integrin interplay and immune cell recruitment. Therapeutic injections of DEL-1 in mice reduces angiotensin II (ANGII)–induced hypertension and cardiac fibrosis. Here we embarked to understanding how endogenous DEL-1 shapes the temporal interplay between inflammation, hemodynamic stress, and myocardial remodeling during hypertension.
Methods:
To investigate the temporal progression of a hypertensive phenotype, male DEL-1 KO mice and age-matched WT controls were infused with ANGII (0.75mg/kg/d), using osmotic minipumps for two weeks to induce hypertension and cardiac remodeling. Mice were examined at three days, one week and two weeks after induction of hypertension for changes in blood pressure using a tail cuff as well as cardiac function and morphology via echocardiography. At each time point organs were also analysed for fibrosis and immune cell recruitment.
Results:
After three days of ANGII treatment, DEL-1 KO mice already showed greater hemodynamic stress compared to their WT counterparts with higher blood pressure (159.3mmHg vs. 150.4mmHg systolic pressure, p<0.01) and impaired systolic function (37.5% vs. 59.6% ejection fraction (EF), p<0.01). Over the course of the treatment blood pressure was consistently higher in DEL-1 KO animals and while concentric hypertrophy transiently developed in both groups the phenotype was ultimately more pronounced in DEL-1 KO mice with greater relative wall thickness (0.59 vs. 0.51, p<0.05) and normalized EF (61.3% vs. 56.8%, p<0.05) two weeks after pump implantation. At this time point, DEL-1 KO myocardial tissue also exhibited advanced remodeling processes with higher collagen I expression and marked interstitial and perivascular fibrosis. Results for inflammatory response to ANGII-challenge are additionally indicating increased immune cell recruitment of myeloid and lymphoid cell lineages from the bone marrow of DEL-1 KO animals.
Conclusions:
In conclusion, the deficiency of endogenous DEL-1 aggravates functional and structural deterioration under pressure overload, linking loss of inflammatory control to maladaptive cardiac remodeling. These findings underline the role of the inflammatory response in hypertension and, in this regard, identify DEL-1 as a crucial regulator preserving cardiac function by balancing hemodynamic stress and immune activation.
