Unravelling the Mechanisms Regulating Endothelial Cell Size and Number to Control Blood Vessel Diameters / Zeenat Diwan.

Format:

Book

Thesis/Dissertation

Author/Creator:

Diwan, Zeenat, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Developmental biology.

Cellular biology.

Molecular biology.

Cell and Molecular Biology--Penn dissertations.

Penn dissertations--Cell and Molecular Biology.

Local Subjects:

Developmental biology.

Cellular biology.

Molecular biology.

Cell and Molecular Biology--Penn dissertations.

Penn dissertations--Cell and Molecular Biology.

Physical Description:

1 online resource (106 pages)

Distribution:

Ann Arbor : ProQuest Dissertations & Theses, 2023

Contained In:

Dissertations Abstracts International 85-08B.

Place of Publication:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.

Language Note:

English

Summary:

Aberrations in blood vessel diameters can disrupt hierarchical vascular patterning and cause severe congenital vascular anomalies, like arteriovenous malformations (AVMs) and venous malformations (VMs). However, despite the plethora of knowledge on the signaling pathways (Endoglin, ALK1, SMAD4, PIK3CA, TIE2) involved in AVM and VM pathology, we still lack an understanding of the early embryonic events regulating vessel hierarchy and arteriovenous shunt formation in vivo.My findings reveal that the artery consistently responds to changes in blood flow and is dependent on flow increase for expansion of its diameter and EC size; while the vein shows context-dependent responses, with one region lacking observable changes, while another responding to an increase or decrease in flow similar to the artery, but to a lesser extent. To unravel the mechanisms underlying the reduced response of vein to flow, I studied zebrafish embryos mutant for endoglin and alk1, genes with differential expression patterns in the artery and vein and whose loss of function results in AVMs. Interestingly, I discovered that both Endoglin and Alk1 were required in the vein to restrict EC size and thus limit venous diameter increases in response to flow. Conversely, utilizing a novel zebrafish pik3ca GOF mutant, I revealed that PI3K signaling promotes EC number increases in the vein.My findings support a model wherein Endoglin and Alk1 render veins less responsive to flow and thus might protect against AVMs during early development. Moreover, my data also reveals the requirement for a balance between Endoglin/Alk1 signaling and PI3K signaling to maintain proper venous diameters through a nuanced regulation of EC size and number. This study thus offers novel insights into the spatiotemporal regulation of vessel hierarchy during early development and highlights the cellular and molecular mechanisms underlying vessel-specific initiation of AVMs in vertebrate models of vascular malformations.

Notes:

Source: Dissertations Abstracts International, Volume: 85-08, Section: B.

Advisors: Siekmann, Arndt; Committee members: Prosser, Benjamin; Kahn, Mark; Mullins, Mary; Good, Matthew.

Department: Cell and Molecular Biology.

Ph.D. University of Pennsylvania 2023.

Local Notes:

School code: 0175

ISBN:

9798381471823

Access Restriction:

Restricted for use by site license.