The ECM provides essential organic components for embryogenesis and tissue maturation. The ECM is conditional; the slightest changes in its physiological state result in ruinous consequences, which might lead to severe defects or even death of the developing embryo (Table 1). In the middle development, the mechanism of dorsal closure could also be a sophisticated method, involving associate degree orchestration of cell–matrix interaction between smooth muscle cells, epithelial tissue cells, and the ECM [20]. A recent study demonstrated that nucleus–cytoskeleton–ECM connections triggered coordinated cardioblast movements, and controlled cardioblast number in Drosophila [21].

Table 1. ECM loss-of-function phenotypes in mammalian development.

Inherent cardiovascular disease is the leading non-infectious rationalization for death in children. It is becoming apparent that many internal organ abnormalities once thought to possess complex etiologies occur because of mutations in biological process management genes [66]. These mutations are manifested at birth as grievous internal organ malformations, or later as subtler internal organ abnormalities. Understanding the role of ECM in internal organ development has vital implications not only for an understanding inherent upset, but also for the chance of internal organ repair through genetic reprogramming of non-cardiac cells to a cardiogenic role strategic location.

The ECM gene expression profiles of embryonic and adult mouse cardiac fibroblasts revealed that higher levels of FN1, collagen genes, TNC, Postn (periostin), and Hapln1 (hyaluronan and proteoglycan link protein 1) were expressed in embryonic than adult hearts [67]. Importantly, embryonic cardiac fibroblasts promote cardiomyocyte proliferation through fibronectin and collagen, involving β1 integrin signaling, leading to myocardial growth and ventricular compaction during cardiogenesis [67]. In an environment rich in abnormal cells and growth factors, activated fibroblasts can produce matrix proteins, proteases and their inhibitors, and regulate matrix metabolism. Due to the pathological maturity, “stress shielding” of fibroblasts through the cross-linked matrix, and macromolecule withdrawal, may lead to quiescence and eventually apoptosis.

Fibulin belongs to a family of five extracellular glycoproteins and mediates the formation of proteoglycan aggregates, elastic fibers, fibronectin microfibrils, basement membrane networks, and supramolecular structures. The expression patterns of biological processes indicate that many fibrins are expressed at epithelial-mesenchymal transition sites during the entire embryogenesis, and the vascular system is related to one of these transition sites [68]. Fibulins 1 and 2 are highly expressed during cardiac valvuloseptal formation. Fibulin 1 is expressed by primordial vascular smooth muscle cells associated with the ventral endothelium of dorsal aortae and developing aortic-arch vessels [52]. In addition, fibulin 2 is expressed by coronary endothelial cells that originate from epicardial cells [69]. Interestingly, fibulin-1 deficiency, but not fibulin 2 deficiency, induced a perinatally lethal phenotype with a defective endothelial basement membrane of small vessels in mice [70]; this may be due to the functional compensation of fibulin 1.

Few studies have investigated the role of TSPs in cardiac development. Increased expression of TSP-1 in the second trimester was demonstrated to cause defects in the cardiovascular system and even embryonic lethality [71]. Conversely, the lack of TSP-4 led to increased ECM production and developmental heart enlargement [65]. As such, it is important to study the modular structures and binding interactions, and the temporal, spatial, and quantitative expression differences of various ECM proteins and their collaborations in cardiovascular health and diseases.

3. ECM in the Programming of Cardiovascular Repair

The adult heart has limited recovery and repair potential, and the loss of myocardial cells due to injury may end in heart disease and death. The cellular biological progression and restraining mechanisms associated with heart development and advancement can repair damaged adult hearts through the “stiring” pathway, which can determine the bioactivity during the entire embryogenesis. Incitement of the differentiation and proliferation of cardiomyocytes, by initiating the mitotic signaling pathway engaged with embryonic heart growth, points to a correlative methodology for heart recovery and repair [72]. Cardiac damage includes arterial sclerosis, myocardial infarction (MI), and ischemic and non-ischemic heart injury, which induces repair by the embryonic cell. Cells reply to the ECM by transforming their microenvironment, which becomes dysregulated in tube-shaped structural diseases, such as high blood pressure, restenosis, and arterial sclerosis [73].

After MI, the ECM dynamic alteration and remodeling propels inflammation and repair [74,75]. The first generation of bioactive matrix fragments activates an unhealthy signal. An extremely plastic tentative matrix formation facilitates blood corpuscle infiltration and activates infarction myofibroblasts [76]. The deposition of matrix cellular macromolecules modulates growth factor signal transduction, and promotes the spatial and temporal regulation of the repair [77]. Temporal scales vary from conformational changes in control of the particle channel gap, to fibrillation over seconds, and end in death. Spatial scales vary from metric linear unit pore sizes in membrane channels and gap junctions, to the meter length scale of the whole cardiovascular system throughout a living patient. Overwhelming changes in the ECM composition are conducive to the pathologic process of cardiac remodeling (Figure 2).

Figure 2. The ECM in the programming of cardiovascular repair and disease. Cardiovascular pathological factors induce abnormal synthesis and release of ECM proteins and ECM signaling, implicated in the process of matrix metalloproteinase (MMP) activation, matrikines production, proliferation, and inflammatory response; this results in cardiovascular remodeling, fibrosis, hypertrophy, and thus heart failure.

4. Epigenetic Regulation of ECM in Heart

Emerging research areas in the ECM field include epigenetic control of gene expression of ECM proteins, or indirectly, by modulating the expression of genes that regulate the synthesis or the degradation of ECM molecules in development and disease onset. Epigenetic changes characterized by RNA and DNA methylation, non-coding RNAs-intervened quality guidelines, and histone adjustments, have been seen in cardiovascular dysfunction and heart recovery (Figure 3), yet the components are indistinct. Knowledge of these aspects will deepen our understanding of ECM regulatory roles in cardiac health and disease, and inform new pharmacological agents targeting ECM-related cardiovascular diseases.

Figure 3. Epigenetic mechanisms of ECM modulation in cardiovascular development and disease. Epigenetic events, including RNA and DNA methylation, histone modifications, and non-coding RNAs mediate ECM gene expression, contributing to cytoskeletal architecture, remodeling, and functional response in heart development. Abnormal epigenetic modification may disrupt ECM homeostasis, leading to cardiovascular pathogenesis.

5. Conclusions

The ECM is a crucial element of the heart. Regulation of ECM structural integrity influences the viscus structure and performance. The strict regulation of temporal and spatial expression, and the proteolytic processing of ECM elements by extracellular proteases are crucial for the development of traditional internal organs. ECM pathological transformation is commonly related to viscus pathology alternative adverse outcomes, while the physiological turnover of ECM is beneficial for the process of tissue regeneration and repair.

Imperfect development in the womb is related to the tendency for cardiovascular disease in adulthood, an idea named “developmental origins of health and disease”. More and more evidence supports the association of epigenetic guidelines with the underlying mechanism. Epigenetic systems, for example, RNA and DNA methylation, histone adjustments, and non-coding RNAs, give a degree of quality guidelines without modifying DNA arrangements. These changes are moderately steady signals, offering possible knowledge into the instrument’s fundamental formative starting points of wellbeing and ailment. Therefore, it is imperative to understand the underlying mechanisms of ECM regulation that control cardiovascular development. Understanding the developmental mechanisms of ECM regulation could contribute to developing therapeutic strategies for cardiovascular disease.