# Complement-Driven Platelet Activation in Pulmonary Vascular Remodeling and Pulmonary Hypertension

> **NIH NIH P01** · UNIVERSITY OF COLORADO DENVER · 2024 · $381,176

## Abstract

PROJECT 4 (ESI) examines the mechanisms by which complement activated platelets drive endothelial
activation and monocyte/macrophage proinflammatory differentiation and recruitment, promoting vascular
remodeling in pulmonary hypertension (PH). Accumulating data from both human and animal studies by our
laboratory and others demonstrate a role for platelets in the initiation and progression of PH, however what drives
platelet activation and how platelets mediate vascular remodeling in PH has not been addressed. Project 4
utilizes several novel and innovative in vivo and in vitro approaches employing genetic and pharmacologic
methods to examine the role of complement mediated platelet activation in two murine models of PH to test the
overall hypothesis that complement-mediated activation of platelets induces endothelial activation and drives the
recruitment and proinflammatory activation of monocytes to the pulmonary vasculature promoting pulmonary
vascular remodeling and pulmonary hypertension. Complement-mediated platelet activation may occur in
inflammatory conditions via complement anaphylatoxin activation of platelets. Whether anaphylatoxins activate
platelets and drive platelet activation in PH is unknown and is the focus of aim 1. Endothelial dysfunction is
central to the pathogenesis of PH, and endothelial cells from patients and animals with PH demonstrate
increased expression of proteins which promote platelet-endothelial adhesion. While the mechanisms for platelet
recruitment and adherence to the endothelium is well described in hemostasis and thrombosis, it is poorly
understood in inflammatory conditions and has not been evaluated in PH. The goal of aim 2 is to determine the
mechanisms of complement mediated platelet activation to platelet endothelial adhesion and how platelet
adhesion to the endothelium promotes endothelial activation in experimental PH. Monocyte and macrophage
recruitment and accumulation within the perivascular/adventitial space is a consistent feature of pulmonary
vascular remodeling associated with PH in both humans and all animal models, however the mechanisms driving
these processes remain poorly understood. Aim 3 will investigate the mechanisms by which complement
activated platelets support the recruitment and activation of blood borne monocytes to the pulmonary vasculature
promoting pulmonary vascular remodeling and pulmonary hypertension. The overall objective of these studies
is to determine whether complement activated platelets drive endothelial and monocyte activation promoting
pulmonary vascular remodeling and PH, setting the stage for future studies targeting the platelet immune
response with novel currently available therapies.

## Key facts

- **NIH application ID:** 10911069
- **Project number:** 5P01HL152961-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Cassidy A Delaney
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $381,176
- **Award type:** 5
- **Project period:** 2020-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911069

## Citation

> US National Institutes of Health, RePORTER application 10911069, Complement-Driven Platelet Activation in Pulmonary Vascular Remodeling and Pulmonary Hypertension (5P01HL152961-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10911069. Licensed CC0.

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