A Distinct Role of the Autonomic Nervous System in Modulating the Function of Lymphatic Vessels under Physiological and Tumor-Draining Conditions

Abstract

Summary Lymphatic vessels (LVs) are important in the regulation of tissue fluid homeostasis and the pathogenesis of tumor progression. We investigated the innervation of LVs and the response to agonists and antagonists of the autonomic nervous system in vivo . While skin-draining collecting LVs express muscarinic, α 1 - and β 2 -adrenergic receptors on lymphatic endothelial cells and smooth muscle cells, intestinal lacteals express only β-adrenergic receptors and muscarinic receptors on their smooth muscle cells. Quantitative in vivo near-infrared imaging of the exposed flank-collecting LV revealed that muscarinic and α 1 -adrenergic agonists increased LV contractility, whereas activation of β 2 -adrenergic receptors inhibited contractility and initiated nitric oxide (NO)-dependent vasodilation. Tumor-draining LVs were expanded and showed a higher innervation density and contractility that was reduced by treatment with atropine, phentolamine, and, most potently, isoproterenol. These findings likely have clinical implications given the impact of lymphatic fluid drainage on intratumoral fluid pressure and thus drug delivery.

Emerging Role of Lymphatics in the Regulation of Intestinal Lipid Mobilization

“…Contraction of isolated rat mesenteric lymphatics is reduced with the activation of the σ1-receptor through an NO-dependent mechanism (Trujillo et al, 2017). SMCs surrounding the intestinal lacteals express β-adrenergic receptors and muscarinic receptors (Bachmann et al, 2019), supporting a mediating role of the vagal nerves that provides dense innervation for intestinal lymphatics and surrounding muscles. Collectively, pumping functions of the larger mesenteric lymphatics and contraction of the lacteals actively participate in lipid drainage in the gut.…”

“…VEGF-C, expressed in a subset of smooth muscle fibers, plays an important role in intestinal lipid absorption and mobilization via regulation of prenatal lymphangiogenesis, maintenance of intestinal lymphatics in adults (Nurmi et al, 2015), and contraction of smooth muscle fibers surrounding the lymphatic vessels, including the lacteals (Gogineni et al, 2013;Choe et al, 2015). Neural control and σ1-receptor may also play a role in lymphatic functions (Trujillo et al, 2017;Bachmann et al, 2019).…”

Sympathetic Nerve Block in Lymphedema Treatment: A Systematic Review

“…Although the sympathetic nerve system modulation of the lymphatic system is relatively well-established, few authors have pursued this mechanism to propose targeted therapies in lymphedema treatment [10-1]. In this systematic literature review, we have shown that different authors have published positive clinical outcomes for sympathetic nerve blocks in the treatment of lymphedema.…”

“…The sympathetic nerve system has been described as a modulator of lymphatic circulation; however, it has not been a topic of debate in the literature about targeted therapies in the treatment of lymphedema [10-11]. Therefore, we conducted a systematic review of publications assessing the use of sympathetic nerve block in lymphedema treatment.…”

Lymphatic Vessels and Their Surroundings: How Local Physical Factors Affect Lymph Flow

“…The intrinsic myogenic activity can be modulated by a complex interplay of different signals, coming from both the vessel lumen and the surrounding interstitium. Moreover, in recent years, literature has provided evidence of a further neuronal modulation exerted by the autonomous nervous system on the intrinsic contractility of lymphatic vessels [ 33 , 34 ], which can introduce a further level of modulation of the response that lymphatic vessels, per se, can provide to stimuli coming from the tissue surrounding them. In this review, we focus our attention on the known physical stimuli and their putative sensing mechanisms localized on the lymphatic vessel wall that can affect spontaneous contractility.…”