Cardiac Microvascular Endothelial Cells in Pressure Overload–Induced Heart Disease

Abstract

Background: Chronic pressure overload predisposes to heart failure, but the pathogenic role of microvascular endothelial cells (MiVEC) remains unknown. We characterized transcriptional, metabolic, and functional adaptation of cardiac MiVEC to pressure overload in mice and patients with aortic stenosis (AS). Methods: In Tie2-Gfp mice subjected to transverse aortic constriction or sham surgery, we performed RNA sequencing of isolated cardiac Gfp + -MiVEC and validated the signature in freshly isolated MiVEC from left ventricle outflow tract and right atrium of patients with AS. We next compared their angiogenic and metabolic profiles and finally correlated molecular and pathological signatures with clinical phenotypes of 42 patients with AS (50% women). Results: In mice, transverse aortic constriction induced progressive systolic dysfunction, fibrosis, and reduced microvascular density. After 10 weeks, 25 genes predominantly involved in matrix-regulation were >2-fold upregulated in isolated MiVEC. Increased transcript levels of Cartilage Intermediate Layer Protein ( Cilp ), Thrombospondin-4 , Adamtsl-2 , and Collagen1a1 were confirmed by quantitative reverse transcription polymerase chain reaction and recapitulated in left ventricle outflow tract-derived MiVEC of AS ( P <0.05 versus right atrium-MiVEC). Fatty acid oxidation increased >2-fold in left ventricle outflow tract-MiVEC, proline content by 130% (median, IQR, 58%–474%; P =0.008) and procollagen secretion by 85% (mean [95% CI, 16%–154%]; P <0.05 versus right atrium-MiVEC for all). The altered transcriptome in left ventricle outflow tract-MiVEC was associated with impaired 2-dimensional-vascular network formation and 3-dimensional-spheroid sprouting ( P <0.05 versus right atrium-MiVEC), profibrotic ultrastructural changes, and impaired diastolic left ventricle function, capillary density and functional status, especially in female AS. Conclusions: Pressure overload induces major transcriptional and metabolic adaptations in cardiac MiVEC resulting in excess interstitial fibrosis and impaired angiogenesis. Molecular rewiring of MiVEC is worse in women, compromises functional status, and identifies novel targets for intervention.

Relative and Absolute Risk to Guide the Management of Pulse Pressure, an Age-Related Cardiovascular Risk Factor

“…Arterial stiffening occurs as a consequence of degradative processes in the wall of the large elastic and muscular arteries driven by the pulsatile BP load, 1 cross-linking of elastin and collagen fibers by nonenzymatic glycation, 19 calcium deposition accompanying atherosclerosis, and changes in the endothelial transcriptome and metabolic dysfunction in response to pressure overload. 20 These degenerative processes, initially asymptomatic, are superimposed on the background of genetic predisposition and lifestyle influences. Assuming reversibility of risk, addressing a risk factor at young age will decrease relative risk with little effect on absolute risk, whereas at the upper end of the age distribution, relative risk will be barely affected, but absolute risk will diminish, thereby enhancing life in calendar years and in quality.…”

Urinary peptidomic profiles to address age-related disabilities: a prospective population study

“…Subsequently, these cells transdifferentiate into α-smooth muscle actin expressing myofibroblasts that secrete the extracellular matrix components required for wound repair in acute injury, but produce excessive extracellular matrix deposition in response to persistent injury. 31 Antifibrotic drugs remain a crucially important unmet medical need, as nearly 45% of all natural deaths in high-income countries are attributed to the complications of chronic fibroproliferative disorders. 32 A detailed review of the molecular pathways of fibrosis and of the refurbished or experimental drugs inhibiting fibrosis extracellularly or intracellularly is beyond the scope of this Article and is summarised elsewhere.…”

“…However, although only 17% of the detected urinary peptides were sequenced, those currently sequenced represented 63% of the total peptide mass. 44 Fourth, proteins with high molecular weight, such as CILP, 31 do not readily pass the cell membrane, remain trapped within the extracellular matrix, and consequently might not be detected by UPP profiling, although they do play a role in pressure-induced left ventricular fibrosis and might be biomarkers of premature ageing.…”

“…Using the Reactome and KEGG databases, the UPP reflected 27 (Reactome) and ten (KEGG) over-represented pathways (q value <0•01; figure 4; appendix pp [29][30][31]. The top pathways identified by Reactome included the biology of collagen, the extracellular matrix (integrin and nonintegrin inter actions), and cellular structural regulation.…”

ADAMTS Proteins and Vascular Remodeling in Aortic Aneurysms

“…ADAMTSL2 is not known to be expressed in VSMC, but rather in other cardiovascular cells, such as cardiomyocytes and dermal blood vessels of human embryos [ 19 ]. Adamtsl2 was found to be overexpressed in microvascular endothelial cells of ventricles in a murine model of transverse aortic constriction [ 72 ]. Using mass spectroscopy on healthy hearts and hearts presenting coronary diseases, ADAMTSL2 was found to be under-expressed in the unhealthy heart [ 73 ].…”