TABLE 1.

Summary table of the signaling pathways that regulate ECM dynamics and associated cell function.

Heart ontogeny/disease	Heart structures	Signaling pathways	ECM remodeling	Cellular impact	References
Embryonic/fetal heart development	Trabeculae	Neuregulin 1	ECM synthesis:    • HA    • Fibronectin	Polarized cardiomyocyte division	Passer et al., 2016; Del Monte-Nieto et al., 2018
		Notch 1	ECM proteolysis:    • ADAMTS1    • MMP2    • HYAL2		Del Monte-Nieto et al., 2018
	Myocardial compaction	Notch 1 Slc39a8 Sema3E/plexinD1	ECM proteolysis:    • ADAMTS1,5,7,9,17    • MMP2    • HYAL2		Del Monte-Nieto et al., 2018; Lin et al., 2018; Sandireddy et al., 2019
	Atrioventricular and valve cushions	BMP2	ECM synthesis:    • HA    • Versican	Cardiac cushion mesenchyme migration	Inai et al., 2013
		BMP4 (inhibition)*	Nephronectin ECM reduced proteolysis:    • HAS2	Restriction of atrioventricular channel differentiation and cardiac jelly swelling	Patra et al., 2011
		TGF-β3	ECM synthesis:    • Periostin    • Collagen 1	Differentiation of the cushion mesenchyme into fibroblasts	Norris et al., 2009
	Outflow tract remodeling	SMAD4	ECM proteolysis:    • MT1-MMP	NCC migration	Jia et al., 2007
	Myocardium	β1-integrin*	Fibronectin	Cardiomyocyte proliferation	Ieda et al., 2009
		YAP/TAZ* ERK*	Soft ECM Agrin		Snider et al., 2008; von Gise et al., 2012; Bassat et al., 2017
Postnatal–adult heart	Myocardium	YAP/TAZ downregulation*	Stiff ECM	Inhibition of cardiomyocyte differentiation	von Gise et al., 2012
Adult heart ischemia	Epicardium, myocardium	TGF-β/Smad3 Hippo downregulation	ECM synthesis:    • Periostin    • Collagen 1	Epicardial cells EMT into fibroblast-like cells Fibroblast activation (myofibroblasts)	Liu et al., 2015; Piersma et al., 2015; Travers et al., 2016; Ramjee et al., 2017

*ECM downstream signaling pathways.