The angiogenic peptide vasodilator adrenomedullin (AM) signals through a G-protein coupled receptor (GPCR) called calcitonin receptor-like receptor (CLR) when the receptor is bound to a novel class of proteins called receptor activity modifying proteins (RAMPs). Using genetically engineered mouse models lacking each of the components of AM signaling, we have consistently identified a rare type of embryonic lethality that is characterized by generalized edema caused by defects in lymphangiogenesis. We hypothesize that AM signaling in endothelial cells is an essential mediator of lymphangiogenesis during embryonic development. Our long-term objective, to define the function of AM signaling during lymphatic vascular development can be met in the following aims:
Specific Aim 1 is geared toward determining the cellular origin of the lymphatic vascular defects and the dosage of AM signaling required for normal lymphangiogenesis. We will generate and characterize novel genetic mouse models to elucidate i) if AM signaling in endothelial cells is necessary for normal lymphangiogenesis ii) if AM signaling in endothelial cells is sufficient to support normal lymphangiogenesis and iii) the minimum dosage of AM required for normal lymphangiogenesis.
Specific Aim 2 will test the hypothesis that AM is a potent modulator of lymphatic endothelial cell proliferation and permeability due to preferential expression of its receptors in lymphatic versus blood endothelial cells. Results from this aim will distinguish genotypic and phenotypic differences between lymphatic and blood vascular cells and will provide a mechanistic basis for the underlying cause of hydrops in the null mouse models.
In Specific Aim 3, we plan to identify genetic pathways that interact with the AM Signaling System to modulate its functions either in healthy or edematous lymphatic vasculature. The functional significance of positively identified pathways will be confirmed through an embryoid body culture system, in vivo corneal neovascularization assays and tail microlymphography. Results from this aim will define the functional consequences of altered AM activity in the lymphatic vasculature and will elucidate how this pathway interacts with other pathways to mediate lymphangiogenesis. By completing these aims we hope to provide novel insights into the processes that govern lymphangiogenesis during development and thus identify a new class of protein targets which can modulate the lymphatic vasculature for the treatment of conditions such as lymphedema or the inhibition of tumor metastasis.

Public Health Relevance

We have demonstrated that genes required for mediating the signal of a potent angiogenic peptide, adrenomedullin, are required for lymphangiogenesis during embryonic development. We plan to elucidate the functions of AM signaling in the lymphatic vasculature. In doing so, we hope to provide novel insights into the processes that govern lymphangiogenesis during development and thus identify a new class of protein targets which can modulate the lymphatic vasculature for the treatment of conditions such as lymphedema or the inhibition of tumor metastasis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
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Tolunay, Eser
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Kechele, Daniel O; Dunworth, William P; Trincot, Claire E et al. (2016) Endothelial Restoration of Receptor Activity-Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy. Hypertension 68:667-77
Wetzel-Strong, Sarah E; Li, Manyu; Klein, Klara R et al. (2014) Epicardial-derived adrenomedullin drives cardiac hyperplasia during embryogenesis. Dev Dyn 243:243-56
Lenhart, Patricia M; Broselid, Stefan; Barrick, Cordelia J et al. (2013) G-protein-coupled receptor 30 interacts with receptor activity-modifying protein 3 and confers sex-dependent cardioprotection. J Mol Endocrinol 51:191-202
Li, Manyu; Schwerbrock, Nicole M J; Lenhart, Patricia M et al. (2013) Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta. J Clin Invest 123:2408-20
Karpinich, Natalie O; Kechele, Daniel O; Espenschied, Scott T et al. (2013) Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis. FASEB J 27:590-600
Wootten, D; Lindmark, H; Kadmiel, M et al. (2013) Receptor activity modifying proteins (RAMPs) interact with the VPAC2 receptor and CRF1 receptors and modulate their function. Br J Pharmacol 168:822-34
Hoopes, Samantha L; Willcockson, Helen H; Caron, Kathleen M (2012) Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice. PLoS One 7:e45261
Barrick, Cordelia J; Lenhart, Patricia M; Dackor, Ryan T et al. (2012) Loss of receptor activity-modifying protein 3 exacerbates cardiac hypertrophy and transition to heart failure in a sex-dependent manner. J Mol Cell Cardiol 52:165-74
Kadmiel, Mahita; Fritz-Six, Kimberly L; Caron, Kathleen M (2012) Understanding RAMPs through genetically engineered mouse models. Adv Exp Med Biol 744:49-60
Karpinich, Natalie O; Hoopes, Samantha L; Kechele, Daniel O et al. (2011) Adrenomedullin Function in Vascular Endothelial Cells: Insights from Genetic Mouse Models. Curr Hypertens Rev 7:228-239

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