Contribution of macrophages to myxomatous valve disease

Abstract

ObjectiveHeart valve interstitial cells (VIC) maintain mature heart valve homeostasis and mediate extracellular matrix (ECM) remodeling during heart valve disease. VICs are of heterogeneous origins, including hematopoietic origin. However, leukocytes remain poorly characterized in heart valves. Interestingly, recent studies reveal infiltration of leukocytes (CD45+) and increased macrophages in human myxomatous mitral valves. Nevertheless, timing and contribution of macrophages during myxomatous valve disease (MVD) are still unknown. Our study will aim to determine if macrophages are required for heart valve homeostasis and contribute to the development of MVD.Methods and resultsLeukocytes are detected in postnatal heart valves and their numbers increase during postnatal valve development. The majority of leukocytes are macrophages as confirmed by flow and lineage tracing of Cx3Cr1 expressing cells. Moreover, two different populations of macrophages with specific location inside the heart valve can be detected in 1 month‐old heart valves. We then examined leukocytes and macrophages in aortic valves of Axin2 KO mice, that exhibit increased Wnt/β‐catenin signaling and myxomatous features by 4 months. Strikingly, CD45+ cells are already increased relative to controls at post‐natal day (P)0 and progressively accumulate in Axin2 KO AoV leaflets prior to extensive ECM remodeling. Increased proinflammatory monocytes (CCR2+) are detected by flow and chemokine CCL3 and CCL7 expression is increased, along with a higher number of macrophages at 1 month indicating macrophage infiltration before disease.ConclusionsOur analysis of Axin2 KO mice reveals for the first time that increased infiltration of leukocytes and macrophages precedes major ECM remodeling during MVD. Ongoing studies involve further characterization of normal and abnormal leukocyte infiltration in AoV by flow cytometry. In addition Cx3cr1‐Cre; Rosa‐DTA mice will be used to deplete macrophages specifically in myxomatous heart valves to determine whether macrophages play a critical role in the development of MVDSupport or Funding InformationAmerican Association of Anatomists, Postdoctoral Fellowship