eprintid: 36468 rev_number: 23 eprint_status: archive userid: 8961 dir: disk0/00/03/64/68 datestamp: 2025-05-06 06:23:58 lastmod: 2025-05-06 06:24:11 status_changed: 2025-05-06 06:23:58 type: doctoralThesis metadata_visibility: show creators_name: Akinbote, Akinola title: Engineered Models of Human Microvasculature: Investigating the Cardiac Microenvironment’s Role in Vascular Remodeling subjects: ddc-500 subjects: ddc-570 subjects: ddc-600 subjects: ddc-610 subjects: ddc-620 divisions: i-140001 adv_faculty: af-14 cterms_swd: Lab on a Chip cterms_swd: European Molecular Biology Laboratory cterms_swd: Biomedicine cterms_swd: capillary endothelium cterms_swd: vascular disease cterms_swd: Vascular endothelial growth factor cterms_swd: Biology cterms_swd: Coronary heart disease cterms_swd: Heart cterms_swd: capillary permeability cterms_swd: capillary flow cterms_swd: In vitro cterms_swd: Tight junction cterms_swd: Gap junction cterms_swd: crosstalk cterms_swd: endothelial cell cterms_swd: fibroblast cterms_swd: blood vessel system cterms_swd: circulatory disorder cterms_swd: blood circulation cterms_swd: blood vessel cterms_swd: Myocardial ischemia cterms_swd: sex hormones cterms_swd: hormones cterms_swd: estrogens cterms_swd: progesterone cterms_swd: progesterone receptor cterms_swd: extracellular matrix cterms_swd: stroma note: Dr. Kristina Haase was my direct supervisor at EMBL Barcelona. | The thesis defense committee was composed of: Prof. Dr. Markus Hecker Dr. Vikas Trivedi Prof.Dr. Stefan Wolf Dr. Mahak Singhal | The thesis advisory committee was composed of: Prof. Dr. Markus Hecker Dr. Vikas Trivedi Dr. Theodore Alexandrov Dr. Gregana Dobreva abstract: Studying the myocardial microvasculature has been challenging, in part, due to technical imaging limitations in vivo and limited physiologically relevant in vitro models. This thesis reports the development of two on-chip models of human microvasculature to study the impact of the tissue microenvironment on cardiac vascular remodeling—with a specific focus on the contributions of stromal cells, cardiomyocytes, and female sex hormones in regulating microvascular behavior. First, the effect of vascular-stromal crosstalk was studied by assessing the impact of tissue-specific co- cultured fibroblasts on microvascular development. The results presented herein, demonstrate that fibroblasts impact microvascular morphology by increasing branch density while decreasing vessel diameter. Cardiac fibroblasts, unlike lung fibroblasts, cause a reduction in vascular barrier function. Moreover, lung and cardiac fibroblasts had a differential response to TGFβ1, mimicking different aspects of fibrosis on-chip. This published first work highlighted the importance of fibroblasts in developing tissue-specific models for vascular research. Next, a 3D model that mimics coronary microvascular structure and barrier function was developed to explore vascular-myocyte crosstalk. Human-induced pluripotent stem cell (hiPSC)-derived cardiac spheroids (CS) were co-cultured with cardiac microvasculature to assess the impact of myocyte crosstalk on microvessel development. Cardiomyocytes altered vessel morphology and improved barrier function in a spatially dependent manner. This vascularized cardiac model was used to investigate the cardioprotective roles of the sex hormones estrogen (E2) and progesterone (P4) under inflammatory conditions. Pre-treatment with these hormones preserves endothelial barrier integrity during TNFα-induced inflammation, potentially by modulating endothelin-1 secretion. Overall, these models highlight the critical role of cellular crosstalk and the tissue microenvironment in vascular development and showcase their utility in modeling vascular perturbations. date: 2026 id_scheme: DOI id_number: 10.11588/heidok.00036468 fp7_project_id: 101040977 own_urn: urn:nbn:de:bsz:16-heidok-364682 date_accepted: 2025-04-11 advisor: HASH(0x559de79064f0) language: eng bibsort: AKINBOTEAKENGINEERED20250425 full_text_status: restricted place_of_pub: Heidelberg citation: Akinbote, Akinola (2026) Engineered Models of Human Microvasculature: Investigating the Cardiac Microenvironment’s Role in Vascular Remodeling. [Dissertation] document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/36468/1/Thesis_Akinola_Akinbote_final.pdf