Atrioventricular valve development: New perspectives on an old theme

Abstract

Atrioventricular valve development commences with an EMT event whereby endocardial cells transform into mesenchyme. The molecular events that induce this phenotypic change are well understood and include many growth factors, signaling components, and transcription factors. Besides their clear importance in valve development, the role of these transformed mesenchyme and the function they serve in the developing prevalve leaflets is less understood. Indeed, we know that these cells migrate, but how and why do they migrate? We also know that they undergo a transition to a mature, committed cell, largely defined as an interstitial fibroblast due to their ability to secrete various matrix components including collagen type I. However, we have yet to uncover mechanisms by which the matrix is synthesized, how it is secreted, and how it is organized. As valve disease is largely characterized by altered cell number, cell activation, and matrix disorganization, answering questions of how the valves are built will likely provide us with information of real clinical relevance. Although expression profiling and descriptive or correlative analyses are insightful, to advance the field, we must now move past the simplicity of these assays and ask fundamental, mechanistic based questions aimed at understanding how valves are ‘built”. Herein we review current understandings of atrioventricular valve development and present what is known and what isn’t known. In most cases, basic, biological questions and hypotheses that were presented decades ago on valve development still are yet to be answered but likely hold keys to uncovering new discoveries with relevance to both embryonic development and the developmental basis of adult heart valve diseases. Thus, the goal of this review is to remind us of these questions and provide new perspectives on an old theme of valve development.

Osteogenesis imperfecta

“…Thus, altered type I collagen synthe sis can affect their biomechanical properties 181 , leading, in rare cases, to aortic dissection 182 . Most commonly reported cardiac abnormalities are aortic root dilation 183 and left sided valvular regurgitation, and, occasionally, right sided valve pathologies [184][185][186] .…”

Cilia and Ciliopathies in Congenital Heart Disease

“…This triggers receptor-mediated endocytosis involving clathrin-coated vesicles, leading to downstream activation of SMAD phosphorylation (Clement et al 2013). The essential role of TGF-b/BMP signaling in CHD is well described via in vitro and in vivo analyses of chick and mouse embryos, and also with the examination of knockout mouse models (Combs and Yutzey 2009;de Vlaming et al 2012;Kruithof et al 2012;von Gise and Pu 2012). These studies show TGF-b/BMP signaling has multiple roles in cardiovascular development that include the regulation of both endocardial EMT and endocardial cushion development (Potts and Runyan 1989;Camenisch et al 2002).…”

How to Make a Heart Valve: From Embryonic Development to Bioengineering of Living Valve Substitutes

“…Remodeling of the primitive ECM into a highly organized and stratified ECM is strongly influenced by hemodynamic stimuli. The developmental mechanisms that coordinate VIC specialization and ECM organization during valvulogenesis remain uncertain (de Vlaming et al 2012). …”