Intermedin Enlarges the Vascular Lumen by Inducing the Quiescent Endothelial Cell Proliferation

Wang, Lijun; Xiao, Fei; Kong, Lingmiao; Wang, Denian; Li, Hongyu; Yue, Wei; Chun, Tae‐Wook; Zhao, Huan; Zhang, Ting; Cao, Guiqun; Zhang, Kang; Wei, Yuquan; Yang, Huiling; Zhang, Wei

doi:10.1161/atvbaha.117.310317

Cited by 33 publications

(41 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Wang et al addressed this question using intermedin-null mice. 36 Intermedin, also called adrenomedulin-2, is a member of calcitonin gene-related peptide family that includes calcitonin, adrenomedullin, and amylin. 37 These peptide hormones initiate signaling via binding to calcitonin receptor-like receptors and signal propagation is controlled by three receptor activity-modifying proteins called RAMPs.…”

Section: Endothelial Control Of Vascular Lumen Diametermentioning

confidence: 99%

“…39 Using CRISPR/Cas9 to generate intermedin (IMD)-deficient mice, together with experiments carried out in vitro , Wang et al was able to show that IMD promotes increased vascular lumen size by stimulating the proliferation of confluent endothelial cells while maintaining organized cell-cell contacts with no significant changes in overall cell shape. 36…”

Section: Endothelial Control Of Vascular Lumen Diametermentioning

confidence: 99%

See 1 more Smart Citation

Vascular Development

Majesky

2018

ATVB

View full text Add to dashboard Cite

The vascular system forms as a branching network of endothelial cells that acquire identity as arterial, venous, hemogenic, or lymphatic. Endothelial specification depends on gene targets transcribed by Ets domain-containing factors, including Ets variant gene 2 (Etv2), together with the activity of chromatin remodeling complexes containing Brahma-related gene-1 (Brg1). Once specified and assembled into vessels, mechanisms regulating lumen diameter and axial growth ensure that the structure of the branching vascular network matches the need for perfusion of target tissues. In addition, blood vessels provide important morphogenic cues that guide or direct the development of organs forming around them. As the embryo grows and lumen diameters increase, smooth muscle cells (SMCs) wrap around the nascent vessel walls to provide mechanical strength and vasomotor control of the circulation. Increasing mechanical stretch and wall strain promote SMC differentiation via coupling of actin cytoskeletal remodeling to myocardin and serum response factor-dependent transcription. Remodeling of artery walls by developmental signaling pathways reappears in postnatal blood vessels during physiological and pathological adaptation to vessel wall injury, inflammation or chronic hypoxia. Recent reports providing insights into major steps in vascular development are reviewed here with a particular emphasis on studies that have been recently published in Arteriosclerosis, Thrombosis, and Vascular Biology.

show abstract

Section: Endothelial Control Of Vascular Lumen Diametermentioning

confidence: 99%

Section: Endothelial Control Of Vascular Lumen Diametermentioning

confidence: 99%

Vascular Development

Majesky

2018

ATVB

View full text Add to dashboard Cite

show abstract

“…Earlier studies have shown that ADM plays critical roles in the regulation of cardiovascular development, vasotone, endothelial barrier integrity, and tumor angiogenesis [3, 9–29]. Likewise, ADM2 is important for the regulation of vascular lumen enlargement, and exerts vaso- and cardio-protective effects in animals with hypertension, heart failure, ischemia reperfusion injury, obesity, or insulin resistance [30–33]. By contrast, CGRPs are important for the regulation of nociception, hyperalgesia, and allodynia [34–37].…”

Section: Introductionmentioning

confidence: 99%

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors

Chang

Hsu²

2019

PLoS ONE

View full text Add to dashboard Cite

CGRP, adrenomedullin (ADM), and adrenomedullin 2 (ADM2) family peptides are important neuropeptides and hormones for the regulation of neurotransmission, vasotone, cardiovascular morphogenesis, vascular integrity, and feto‒placental development. These peptides signal through CLR/RAMP1, 2 and 3 receptor complexes. CLR/RAMP1, or CGRP receptor, antagonists have been developed for the treatment of migraine headache and osteoarthritis pain; whereas CLR/RAMP2, or ADM receptor, antagonists are being developed for the treatment of tumor growth/metastasis. Based on the finding that an acylated chimeric ADM/ADM2 analog potently stimulates CLR/RAMP1 and 2 signaling, we hypothesized that the binding domain of this analog could have potent inhibitory activity on CLR/RAMP receptors. Consistent with this hypothesis, we showed that acylated truncated ADM/ADM2 analogs of 27–31 residues exhibit potent antagonistic activity toward CLR/RAMP1 and 2. On the other hand, nonacylated analogs have minimal activity. Further truncation at the junctional region of these chimeric analogs led to the generation of CLR/RAMP1-selective antagonists. A 17-amino-acid analog (Antagonist 2–4) showed 100-fold selectivity for CLR/RAMP1 and was >100-fold more potent than the classic CGRP receptor antagonist CGRP8-37. In addition, we showed (1) a lysine residue in the Antagonist 2–4 is important for enhancing the antagonistic activity, (2) an analog consisted of an ADM sequence motif and a 12-amino-acid binding domain of CGRP exhibits potent CLR/RAMP1-inhibitory activity, and (3) a chimeric analog consisted of a somatostatin analog and an ADM antagonist exhibits dual activities on somatostatin and CLR/RAMP receptors. Because the blockage of CLR/RAMP signaling prevents migraine pain and suppresses tumor growth/metastasis, further studies of these analogs, which presumably have better access to the tumor microenvironment and nerve endings at the trigeminal ganglion and synovial joints as compared to antibody-based therapies, may lead to the development of better anti-CGRP therapy and alternative antiangiogenesis therapy. Likewise, the use of bifunctional somatostatin-ADM antagonist analogs could be a promising strategy for the treatment of high-grade neuroendocrine tumors by targeting an antiangiogenesis agent to the neuroendocrine tumor microenvironment.

show abstract

“…AM2/IMD is widely expressed, and its actions include hypothalamic-pituitary-adrenal axis activation (6); protective effects in hypertension, heart attack, heart failure, and ischemia reperfusion injury (3,(7)(8)(9)(10)(11)(12); and promotion of adipocyte browning and reduction of insulin resistance and obesity (13,14). An AM2/IMD knockout mouse revealed a role for the peptide in vascular lumen enlargement during both normal and pathological angiogenesis by promoting endothelial cell proliferation (15). In humans, plasma AM2/IMD is elevated in heart failure (16), and a gene polymorphism is associated with hypertension, kidney dysfunction, and cerebrovascular lesions (17).…”

mentioning

confidence: 99%

Structure–function analyses reveal a triple β-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design

Roehrkasse

Booe

Lee

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

The cardioprotective vasodilator peptide adrenomedullin 2/intermedin (AM2/IMD) and the related adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) signal through three heterodimeric receptors comprising the calcitonin receptor-like class B G protein-coupled receptor (CLR) and a variable receptor activity-modifying protein (RAMP1, -2, or -3) that determines ligand selectivity. The CGRP receptor (RAMP1:CLR) favors CGRP binding, whereas the AM (RAMP2:CLR) and AM (RAMP3:CLR) receptors favor AM binding. How AM2/IMD binds the receptors and how RAMPs modulate its binding is unknown. Here, we show that AM2/IMD binds the three purified RAMP-CLR extracellular domain (ECD) complexes with a selectivity profile that is distinct from those of CGRP and AM. AM2/IMD bound all three ECD complexes but preferred the CGRP and AM receptor complexes. A 2.05 Å resolution crystal structure of an AM2/IMD antagonist fragment-bound RAMP1-CLR ECD complex revealed that AM2/IMD binds the complex through a unique triple β-turn conformation that was confirmed by peptide and receptor mutagenesis. Comparisons of the receptor-bound conformations of AM2/IMD, AM, and a high-affinity CGRP analog revealed differences that may have implications for biased signaling. Guided by the structure, enhanced-affinity AM2/IMD antagonist variants were developed, including one that discriminates the AM and AM receptors with ∼40-fold difference in affinities and one stabilized by an intramolecular disulfide bond. These results reveal differences in how the three peptides engage the receptors, inform development of AM2/IMD-based pharmacological tools and therapeutics, and provide insights into RAMP modulation of receptor pharmacology.

show abstract

Intermedin Enlarges the Vascular Lumen by Inducing the Quiescent Endothelial Cell Proliferation

Abstract: Our findings suggest a novel mechanism that may explain how quiescent ECs overcome the contact inhibition and regain the ability to proliferate for continuous vascular lumen enlargement.

Cited by 33 publications

References 35 publications

Vascular Development

Vascular Development

Development of chimeric and bifunctional antagonists for CLR/RAMP receptors

Structure–function analyses reveal a triple β-turn receptor-bound conformation of adrenomedullin 2/intermedin and enable peptide antagonist design

Contact Info

Product

Resources

About