Induction of Cardiac Angiogenesis Requires Killer Cell Lectin-Like Receptor 1 and α4β7 Integrin Expression by NK Cells

Abstract

Recent findings indicate that NK cells are involved in cardiac repair following myocardial infarction. The aim of this study is to investigate the role NK cells in infarct angiogenesis and cardiac remodeling. In normal C57BL/6 mice, myelomonocytic inflammatory cells invaded infarcted heart within 24 h followed by a lymphoid/NK cell infiltrate by day 6, accompanied by substantial expression of IL-2, TNF-α, and CCL2. In contrast, NOD SCID mice had virtually no lymphoid cells infiltrating the heart and did not upregulate IL-2 levels. In vitro and in vivo, IL-2–activated NK cells promoted TNF-α–stimulated endothelial cell proliferation, enhanced angiogenesis and reduced fibrosis within the infarcted myocardium. Adoptive transfer of IL-2–activated NK cells to NOD SCID mice improved post-myocardial infarction angiogenesis. RNA silencing technology and neutralizing Abs demonstrated that this process involved α4β7 integrin/VCAM-1 and killer cell lectin-like receptor 1/N-cadherin–specific binding. In this study, we show that IL-2–activated NK cells reduce myocardial collagen deposition along with an increase in neovascularization following acute cardiac ischemia through specific interaction with endothelial cells. These data define a potential role of activated NK cells in cardiac angiogenesis and open new perspectives for the treatment of ischemic diseases.

Impaired Natural Killer Cell Phenotype and Function in Idiopathic and Heritable Pulmonary Arterial Hypertension

“…11,26 Although dNK cells are thought to be a distinct subset to circulating NK cell populations, with a unique capacity to influence vascular structure, circulating NK cells have also been implicated in the support of collateral artery formation in a murine model of hindlimb ischemia 9 and in cardiac angiogenesis following myocardial infarction. 10 Our finding of increased MMP-9 gene expression and enzymatic activity in circulating NK cells from PAH patients provides a potential mechanism by which these cells can directly influence pathological pulmonary vascular remodeling. This finding is supported by previous work reporting elevated MMP-2 and MMP-9 in the lungs of rats with monocrotaline-induced pulmonary hypertension.…”

Natural killer cells in inflammatory heart disease

“…The effect of this transfer was limited in the absence of NK cells [1]. NK cells have also been shown to interact with cardiac endothelial cells post-MI to increase vascularization and angiogenesis [73, 74]. However, attempts by other groups to repeat these findings were unsuccessful, with most groups finding that the majority of HSCs differentiated into neutrophils with limited establishment in the heart as resident cells [75–77].…”

A Novel Pro-Angiogenic Function for Interferon-γ–Secreting Natural Killer Cells

“…[5][6][7] In addition, recently, NK cells have been ascribed functions in physiological processes, such as induction of vascular growth, remodeling, and secretion of angiogenic factors. [8][9][10][11] However, the precise mechanisms by which NK cells induce inflammatory angiogenesis, especially in the eye, remain unclear.…”