EARLY CHANGES IN THE CALCITONIN-GENE-RELATED PEPTIDE (CGRP) CONTENT OF PULMONARY ENDOCRINE-CELLS CONCOMITANT WITH VASCULAR REMODELING IN THE HYPOXIC RAT

Morphologic changes are reported to occur in rat lung vasculature afte r 3 days of hypoxia. We have previously shown that immunoreactivity fo r the vasodilator calcitonin gene-related peptide (CGRP) is increased in pulmonary endocrine cells by 7 days of hypoxia. Because these cells may be among the earliest mediators of the hypoxic response, we exami ned endocrine cell CGRP content in rat lung after 0, 2, 4, and 8 h and 1, 5, 10, 15, 20, 28, and 35 days of normobaric hypoxia, using optima l and supraoptimal dilutions of CGRP antibodies to demonstrate changes in CGRP immunoreactivity. This was compared with temporal changes in pulmonary vascular smooth muscle after 1, 5, and 20 days of hypoxia ex posure by evaluating vascular immunoreactivity for alpha-smooth muscle actin (alpha-SM actin), platelet-derived growth factor (PDGF) beta-re ceptor, and proliferating cell nuclear antigen (PCNA). Significant inc reases in endocrine cell CGRP immunoreactivity were found after 4 h of hypoxia, and levels increased up to 1 day, followed by a decrease (at 5 days) and then a progressive increase up to 35 days. After 1 day of hypoxia, the number of vessels displaying immunoreactivity for alpha- SM actin, PDGF beta-receptor, and PCNA were also significantly increas ed. Whereas PDGF beta-receptor and PCNA returned to control values by day 20, alpha-SM actin reached a plateau that persisted until 20 days. The results indicate that modulation of endocrine cell CGRP content i n response to hypoxia is rapid and characterized by a significant and persistent increase, paralleled by a proliferation of vascular cells l eading to vascular muscularization. Furthermore, this vessel remodelin g begins earlier than has been previously reported, possibly involving PDGF through the vascular expression of its beta-receptor. Thus, thes e early events could be related to the development of hypoxia-induced pulmonary hypertension.