Coronary veins determine the pattern of sympathetic innervation in the developing heart

Abstract

SUMMARYAnatomical congruence of peripheral nerves and blood vessels is well recognized in a variety of tissues. Their physical proximity and similar branching patterns suggest that the development of these networks might be a coordinated process. Here we show that large diameter coronary veins serve as an intermediate template for distal sympathetic axon extension in the subepicardial layer of the dorsal ventricular wall of the developing mouse heart. Vascular smooth muscle cells (VSMCs) associate with large diameter veins during angiogenesis. In vivo and in vitro experiments demonstrate that these cells mediate extension of sympathetic axons via nerve growth factor (NGF). This association enables topological targeting of axons to final targets such as large diameter coronary arteries in the deeper myocardial layer. As axons extend along veins, arterial VSMCs begin to secrete NGF, which allows axons to reach target cells. We propose a sequential mechanism in which initial axon extension in the subepicardium is governed by transient NGF expression by VSMCs as they are recruited to coronary veins; subsequently, VSMCs in the myocardium begin to express NGF as they are recruited by remodeling arteries, attracting axons toward their final targets. The proposed mechanism underlies a distinct, stereotypical pattern of autonomic innervation that is adapted to the complex tissue structure and physiology of the heart.

Netrin-1 controls sympathetic arterial innervation

“…Netrin-1 was not expressed in the heart, and cardiac innervation was normal in Ntn1 mutants. Interestingly, a growing body of evidence indicates that innervation of the heart and large arteries is regulated by other molecules, including NGF and the axon guidance molecule Sema3A and its receptor Nrp1 (41)(42)(43). Therefore, sympathetic innervation of cardiovascular targets may be regulated by specific combinations of guidance molecules: Sema3A/Nrp1 for the heart and large arteries and netrin/DCC for resistance arteries.…”

The epicardium as modulator of the cardiac autonomic response during early development

“…Disturbing epicardial outgrowth results in abnormal development of the coronary vasculature [36]. The hampered response to epinephrine described in the current study could possibly be explained by disruption of the earliest stages of blood vessel formation and NGF production, which is required for normal development of the autonomic nervous system [41].…”

“…Finally, recent work showed that normal development of the cardiac veins is required for normal development of the sympathetic nervous system of the heart [41]. This process is driven by nerve growth factor (NGF), secreted by vascular smooth muscle cells in subepicardial blood vessels [41].…”

“…This process is driven by nerve growth factor (NGF), secreted by vascular smooth muscle cells in subepicardial blood vessels [41]. Interestingly, the smooth muscle cells in the coronary vasculature derive from the epicardium after EMT [42,43].…”

Analysis of Coronary Vessels in Cleared Embryonic Hearts

“…Vessels fated to form arteries and capillaries are localized deep within the walls of both the ventricles and the aorta [1][2][3] . However, whilst fluorescent labeling of cells combined with laser-scanning confocal microscopy can provide high resolution images of wholemount-labeled superficial venous/lymphatic vessels 4,5 , the depth of imaging is limited by optical penetration. High-resolution imaging of capillaries and arteries throughout the whole depth of the heart is therefore not possible without some form of tissue clearing.…”