Semaphorins in cardiovascular medicine

•Semaphorins regulate specific aspects of cardiovascular development. •Semaphorins have a role in congenital cardiovascular diseases. •Semaphorins are new targets for innovative therapies in vascular medicine. •The role of semaphorins in diseases with endothelial dysfunctions are being explored. During organogenesis, patterning is primarily achieved by the combined actions of morphogens. Among these, semaphorins represent a general system for establishing the appropriate wiring architecture of biological nets. Originally discovered as evolutionarily conserved steering molecules for developing axons, subsequent studies on semaphorins expanded their functions to the cardiovascular and immune systems. Semaphorins participate in cardiac organogenesis and control physiological vasculogenesis and angiogenesis, which result from a balance between pro- and anti-angiogenic signals. These signals are altered in several diseases. In this review, we discuss the role of semaphorins in vascular biology, emphasizing the mechanisms by which these molecules control vascular patterning and lymphangiogenesis, as well as in genetically inherited and degenerative vascular diseases. During organogenesis, patterning is primarily achieved by the combined actions of morphogens. Among these, semaphorins represent a general system for establishing the appropriate wiring architecture of biological nets. Originally discovered as evolutionarily conserved steering molecules for developing axons, subsequent studies on semaphorins expanded their functions to the cardiovascular and immune systems. Semaphorins participate in cardiac organogenesis and control physiological vasculogenesis and angiogenesis, which result from a balance between pro- and anti-angiogenic signals. These signals are altered in several diseases. In this review, we discuss the role of semaphorins in vascular biology, emphasizing the mechanisms by which these molecules control vascular patterning and lymphangiogenesis, as well as in genetically inherited and degenerative vascular diseases. the process describing the transformation of the primitive vascular plexus formed by vasculogenesis into hierarchically organized arteries, capillaries, and veins. This ability is maintained in adult life to sustain the growth of the organs and characterizes several pathological settings. Angiogenesis occurs by sprouting from pre-existing capillaries and requires proteolytic digestion of the extracellular matrix, endothelial cell (EC) migration and proliferation, and their further differentiation in capillaries with a patent lumen. A second mechanism is intussusception. Protrusion of opposing microvascular walls into the capillary lumen creates a bridge between ECs, which represents the template to from a transluminar pillar leading to the formation of two vessels. Angioblasts differentiated from the mesoderm of the pharyngeal arches produce six pairs of aortic arches, which are connected to the dorsal aorta and developing cardiac outflow tract (OFT) through the aortic sac. As the caudal vessels become apparent, the most rostral vessels largely disappear and the definitive pattern of the great vessels is gradually established. the first intra-embryonic blood vessels to arise in the trunk. Primary dorsal aortae comprise a pair of longitudinal vessels in which the anterior ends are connected to the nascent heart via the OFT and the posterior parts are linked to vitelline arteries at the umbilicus level. The left dorsal aorta creates the arch and the descending aorta in adults, whereas the right disappears. two embryonic areas involved in heart development. The heart develops from a primitive heart tube, which is derived from two primary heart fields located in the lateral plate mesoderm. When this tube undergoes elongation and rightward looping, it represents a scaffold to host the cardiac precursors that are derived from a second heart field consisting of cells located in the pharyngeal mesoderm. These cells contribute to the final shape of the left ventricle, the formation of the OFT, and most of the right ventricle and atrias. a multipotent cell population that arises on the dorsal neural tube during development. Neural crest cells (NCCs) delaminate and migrate through the body forming peripheral nervous system and melanocytes. The ectomesenchyme originates from a cranial region of NC and is the source of head and neck tissues. A subpopulation of ectomesenchyle represents the cardiac NC for the importance in different aspects of cardiovascular development. Cardiac NCCs support the development and patterning of the persisting aortic arch arteries into the great arteries and form their smooth muscle layers. They participate in the OFT septation, dividing the common arterial outflow into the aorta and pulmonary trunk. Finally, NCCs that give rise to parasympathetic innervation of the heart influence the recruitment of precursors from the second heart field to the OFT. pulmonary veins originate from the midpharyngeal mesenchyme that surrounds the forming lung buds. The first connection of the pulmonary circulation with the heart is mediated by a solitary pulmonary vein, which enters the primary atrium and precedes chamber septation. Subsequent remodeling allows for the final arrangement with four venous orifices the early formation of the primitive capillary network, which occurs in extra-embryonic and embryonic areas. Angioblasts are the first vascular precursors, which stem from the mesoderm and bear early markers of endothelial lineage. Their commitment and differentiation are regulated by instructive signals from the endoderm. Angioblasts coalesce, form a lumen, and fuse to form a plexus of small blood vessels.