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Targeted blocking of gene expression for CGRP receptors elevates pulmonary artery pressure in hypoxic rats
1Department of Comparative Biosciences, University of Wisconsin-Madison, School of Veterinary Medicine, AHABS Bldg., 1656 Linden Drive, Madison, WI 53706, USA.
Abstract:
We previously described the protection by calcitonin gene-related peptide (CGRP) against hypoxic pulmonary hypertension. Here, we examine the roles of its putative receptor RDC-1 and receptor activity-modifying protein (RAMP) 1 in mediating this protection by selectively inhibiting their synthesis. RAMP1 is an accessory protein for another putative CGRP receptor, calcitonin receptor-like receptor. Antisense oligodeoxyribonucleotides (ASODNs, 5 mg.kg-1.day-1 or 5 and 10 mg.kg-1.day-1 for RDC-1) targeting RAMP1 and RDC-1 mRNAs were chronically infused to the pulmonary circulation of male Sprague-Dawley rats during 7 days of normoxia or hypobaric hypoxia (380 mmHg), and alpha-CGRP ASODN was used as a technical control. CGRP, RAMP1, and RDC-1 ASODNs significantly elevated pulmonary artery pressure (PPA) in chronic hypoxic rats compared with hypoxic mismatched ASODN (MMODN) and saline vehicle controls. CGRP and RAMP1 ASODNs raised PPA in normoxic rats briefly exposed to 10% O2 above MMODN and saline controls. Moreover, normoxic rats treated with CGRP ASODN had higher basal pulmonary vascular tone compared with controls. These data confirm the protective role of CGRP in the pulmonary circulation and suggest that endogenous RAMP1 and RDC-1 are essential in regulation of PPA in hypoxia. This is the first in vivo evidence supporting RDC-1 and RAMP1 as functional CGRP receptor and receptor component.
Insights
Calcitonin gene-related peptide (CGRP) protects against hypoxic pulmonary hypertension. This study shows that its receptor components, RDC-1 and receptor activity-modifying protein 1 (RAMP1), are essential for this protective effect in vivo.
Area of Science:
- Cardiovascular Physiology
- Pulmonary Hypertension Research
- Molecular Endocrinology
Background:
- Calcitonin gene-related peptide (CGRP) has a known protective role in hypoxic pulmonary hypertension.
- The specific receptor components mediating CGRP's protective effects in the pulmonary circulation were not fully elucidated.
- RDC-1 and receptor activity-modifying protein 1 (RAMP1) are putative components of a CGRP receptor.
Purpose of the Study:
- To investigate the in vivo roles of RDC-1 and RAMP1 in mediating CGRP's protection against hypoxic pulmonary hypertension.
- To determine if RDC-1 and RAMP1 are essential components of a functional CGRP receptor in the pulmonary vasculature.
- To provide evidence for RDC-1 and RAMP1 as functional CGRP receptor components.
Main Methods:
- Utilized antisense oligodeoxyribonucleotides (ASODNs) to selectively inhibit the synthesis of RAMP1 and RDC-1 mRNAs in Sprague-Dawley rats.
- Administered ASODNs via chronic infusion into the pulmonary circulation during normoxia and hypobaric hypoxia (380 mmHg) for 7 days.
- Measured pulmonary artery pressure (PPA) and basal pulmonary vascular tone as key physiological outcomes.
Main Results:
- Inhibition of CGRP, RAMP1, or RDC-1 synthesis using ASODNs significantly elevated pulmonary artery pressure (PPA) in rats exposed to chronic hypoxia.
- CGRP and RAMP1 ASODNs also increased PPA in normoxic rats exposed to acute hypoxia (10% O2).
- CGRP ASODN treatment led to higher basal pulmonary vascular tone in normoxic rats, confirming CGRP's role in regulating vascular tone.
Conclusions:
- Endogenous RAMP1 and RDC-1 are critical for regulating pulmonary artery pressure during hypoxia.
- These findings provide the first in vivo evidence supporting RDC-1 and RAMP1 as functional components of a CGRP receptor.
- CGRP plays a vital protective role in the pulmonary circulation, mediated by RDC-1 and RAMP1.