Circulating Levels of Calcitonin Gene-Related Peptide Are Lower in COVID-19 Patients

Laura Ochoa-Callejero; Josune García-Sanmartín; Pablo Villoslada-Blanco; María Íñiguez; Patricia Pérez-Matute; Elisabet Pujadas; Mary E. Fowkes; Rachel Brody; José A. Oteo; Alfredo Martínez


J Endo Soc. 2021;5(3) 

In This Article

Abstract and Introduction


Background: To better understand the biology of COVID-19, we have explored the behavior of calcitonin gene-related peptide (CGRP), an angiogenic, vasodilating, and immune modulating peptide, in severe acute respiratory syndrome coronavirus 2 positive patients.

Methods: Levels of CGRP in the serum of 57 COVID-19 patients (24 asymptomatic, 23 hospitalized in the general ward, and 10 admitted to the intensive care unit) and healthy donors (n = 24) were measured by enzyme-linked immunosorbent assay (ELISA). In addition, to better understand the physiological consequences of the observed variations, we investigated by immunofluorescence the distribution of receptor activity modifying protein 1 (RAMP1), one of the components of the CGRP receptor, in autopsy lung specimens.

Results: CGRP levels were greatly decreased in COVID-19 patients (P < 0.001) when compared to controls, and there were no significant differences due to disease severity, sex, age, or comorbidities. We found that COVID-19 patients treated with proton pump inhibitors had lower levels of CGRP than other patients not taking this treatment (P = 0.001). RAMP1 immunoreactivity was found in smooth muscle cells of large blood vessels and the bronchial tree and in the airways' epithelium. In COVID-19 samples, RAMP1 was also found in proliferating type II pneumocytes, a common finding in these patients.

Conclusions: The lower levels of CGRP should negatively impact the respiratory physiology of COVID-19 patients due to vasoconstriction, improper angiogenesis, less epithelial repair, and faulty immune response. Therefore, restoring CGRP levels in these patients may represent a novel therapeutic approach for COVID-19.


The COVID-19 pandemic has developed into the major challenge to global health in our lifetime. This disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and it affects people in different ways, ranging from asymptomatic disease to severe pneumonia that may require oxygen therapy and even leading to death.[1] At present, there is no specific treatment for the disease and only prevention strategies such as promoting social distance, increasing general hygiene, and applying symptomatic remedies can reduce COVID-19 impact.[2] Also, vaccine development is progressing rapidly.[3] A full understanding of the biology implicated in the evolution of the disease may provide new ideas for the treatment and management of patients. In this regard, interesting data are arising from the study of autopsy specimens.[4] Among other pathological findings, the occurrence of angiogenesis in the lung of seriously affected patients has been reported.[5] A recent article has studied the potential pro-angiogenic molecules whose expression is upregulated in COVID-19 patients.[6] Among those markers, we were especially interested in receptor activity modifying protein 1 (RAMP1) which, in combination with the calcitonin receptor-like receptor (CLR), constitutes the receptor for calcitonin gene-related peptide (CGRP).[7]

CGRP is a pro-angiogenic molecule,[8] but it also plays other important roles in the lung including vasoregulation, bronchoprotection, anti-inflammatory actions, and tissue repair,[9,10] all of them very relevant for the evolution of COVID-19 pathogenesis. In the normal lung, CGRP is found in neuroepithelial bodies and in nerve fibers that contact the epithelium, neuroendocrine cells, and smooth muscle.[11] CGRP binding sites have been found in pulmonary blood vessels and the smooth muscle and epithelium of large airways.[12] It has been shown that CGRP promotes the growth of bronchial[13] and alveolar[14] epithelial cells following lung injury, thus acting as a protective mediator in all kinds of experimental procedures involving lung insults.[15]

Another important function for CGRP in the lung is the regulation of the immune system. CGRP expression is enhanced in response to inflammation,[16] and it exerts anti-inflammatory actions by regulating macrophage polarization[17] and by inhibiting dendritic and T cells.[18] CGRP also limits group 2 innate lymphoid cell (ILC2) responses.[19] Depending on the context, this anti-inflammatory potential may be positive or negative for the patient. For instance, the presence of CGRP-positive nerves reduced immunity and thus survival in a model of lethal Staphylococcus aureus pneumonia.[20] In addition, in knock-out models, where either the peptide[21] or the receptor[22] was disrupted, there was a reduction of allergic asthma responses. This involvement with the immune system could be critical for the pathophysiology of COVID-19.[23]

Therefore, our objective was to evaluate the levels of circulating CGRP in COVID-19 patients with different symptoms and to compare them with healthy controls. We also studied the expression of RAMP1 in the lungs of patients who died of COVID-19 and compared them with patients who died by unrelated causes.