Mechanisms of Angiogenesis Process after Pancreatic Islet Cell
Transplantation: Role of Intra-islet Endothelial Cells
Siddharth Narayanan, Gopalakrishnan Loganathan, Maheswaran Dhanasekaran, Michael J Hughes, Stuart K Williams and Appakalai N Balamurugan*
Department of Surgery, University of Louisville, Kentucky, USA
- *Corresponding Author:
- Appakalai N Balamurugan
Clinical Islet Cell Laboratory
Center for Cellular Transplantation
Cardiovascular Innovation Institute
Department of Surgery, University of Louisville
Louisville, KY, USA
Received Date: December 07, 2016; Accepted Date: December 23, 2016; Published Date: January 02, 2017
Citation: Narayanan S, Loganathan G, Dhanasekaran M, Hughes MJ, Williams SK, et al. (2017) Mechanisms of Angiogenesis Process after
Pancreatic Islet Cell Transplantation: Role of Intra-islet Endothelial Cells. J Transplant Technol Res 7: 171. doi:
Copyright: © 2017 Narayanan S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.
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Angiogenic sprouting is a complex, multi-step process involving highly integrated cell behaviours, initial interaction with the environment and signalling pathways. Endothelial cells (ECs) are central to the angiogenic process, with recent insights establishing how these cells communicate with each other and with their microenvironment to form branched vascular networks. Using pancreatic islets as a model for vascularized tissue, this review will present a general overview of EC behaviour dynamics in sprouting angiogenesis, particularly focusing on the interplay between VEGF and Notch pathways. A better understanding of molecular mechanisms associated with intra-islet EC cross-talk and its micro-environment may present exciting new perspectives on islet graft to host revascularization and in supporting islet graft survival.
Transplantation; Endothelial cells; Angiogenesis;
Pancreatic islets are highly vascularized and receive 10% of the
pancreatic blood flow despite comprising of only 1-2% of the overall
tissue mass . Islets represent endocrine “island” clusters, embedded
and scattered within large amounts of exocrine acinar tissue . Most
islets are irregularly shaped spheroids with a size distribution ranging
from 50–200 μm, composed of 800–3,000 cells. In the context of islet
studies and transplantation, 1 islet equivalent (IEQ) is often considered
as a size of 150 mm, consisting of an average 2,500 cells. The cellular
components of the islet include β-cells with the remainder of the islet
comprised of other endocrine cells (including glucagon-secreting α-
cells, somatostatin secreting δ-cells, pancreatic polypeptide-secreting
γ-cells, and ghrelin-producing ε-cells), as well as ECs and support cells
such as pericytes [3-12]. Species heterogeneity exists with respect to
cellular composition of islets. Rodent islets are primarily composed of
β-cells located in the center with other cell types in the periphery,
human islets exhibit interconnected α- and β-cells [3-13,14]. β-cell, the
central regulator of glucose homeostasis is the largest cellular
component of islets in most species [12,13]. Vascular endothelial cells
represent a major cell type present in islets and these cells are
organized into a highly regulated and morphologically unique
microcirculation. Studies using vascular corrosion casts have shown
that 1-3 arterioles feed larger islets . The capillary network within
islets is about five times denser in comparison with exocrine tissue
. The capillary wall is composed of a permeable layer of ECs and
contain ten times more fenestrae than ECs present in the exocrine
pancreas [17,18]. Rapid and adequate revascularization is critical for
survival and function of transplanted islets [19-21]. Unlike whole
organ transplantation where revascularization occurs through surgical
anastomosis of vessels, the revascularization of islets requires the
formation of vessel patencies either through inosculation of host and
recipient microvessels or through neo-vessel penetration into the islet.
The return of islet function depends on reestablishment of new vessels
within islet grafts to derive blood flow from the host vascular system
[22,23]. Transplanted islet grafts initially have a significant reduction in
vascular supply and low oxygen tension in comparison to normal islets
[24-26]. The human islet isolation technique completely severs the islet
vasculature [20,27], the enzymatic digestion step contributing towards
partially disrupting intra-islet ECs [22,28,29]. Revascularization is an
important process for adequate engraftment of islets. Prevascularizing
islets prior to transplantation could potentially improve islet
survivability and function by aiding islet-to-host inosculation .
Studies involving cell and tissue engineering approaches have
considered factors such as pancreatic islet size-dependency , use of
stem cells [32-35], endothelial progenitor cell derived microvesicles
, creating engineered vascular beds and hydrogels [37-39] and
repurposed biological scaffolds  to improve islet revascularization
potential. The angiogenic capacity of islet ECs has been previously
determined . These cells have been shown to support
revascularization of fresh islets by participating in the early processes
of vessel formation [30,42]. Unpublished data from our lab
demonstrates that fresh islets, immediately after isolation, are capable
of forming peri-islet vessels in a 3D-gel construct (Figure 1). The initial
molecular events by which intra-islet ECs result in the formation of
such vessels have not yet been explored. This review will focus on the
VEGF-Notch signalling pathways and their associated molecular
regulation which have been well characterized and shown to play key
roles in endothelial crosstalk critical to proper vessel sprouting.
Figure 1: Islet sprout monitoring in group of human islets in time
Regulation of angiogenesis
VEGF family: critical regulators of angiogenesis: The family of
VEGF (vascular endothelial growth factor) ligands and their receptors
are major regulators of sprouting angiogenesis [43-46]. VEGFs are
critical, as they regulate vessel formation during embryonic
development, play a major role in wound healing and in maintaining
vessel homeostasis in adult organisms. In addition, impaired vessel
function resulting from defects in VEGF ligands or receptors is the
cause of many diseases. VEGF was originally described as vascular
permeability factor (VPF), an activity released by tumor cells that
promotes vascular leakage [43,47-56]. VEGF secretion is stimulated by
tumor, hypoxia, low pH and many other factors. The VEGF binds to its
receptor (VEGFR) located on the blood vessel ECs. The ECs upon
activation produce enzymes and other molecules for EC growth and
proliferation. Other effects include mobilization of endothelial
progenitor cells from bone marrow, increased vascular permeability
and tissue factor induction. The VEGF family comprises seven secreted
glycoproteins that are designated VEGF-A, VEGF-B, VEGF-C, VEGFD,
VEGF-E, placental growth factor (PlGF) and VEGF-F [57-59].
VEGF-A, the most well studied factor within the VEGF family, is
expressed in the extra-embryonic endoderm and mesoderm as blood
islands, and within the intra-embryonic endoderm at E8.5  (Table
|Type of VEGF
||Role in regulating/modulating ECs
||Most potent pro-angiogenic protein described to date, implicated in both vasculogenesis and angiogenesis. It induces proliferation, sprouting and tube formation of ECs.
|Is a potent survival factor for ECs and has been shown to induce the expression of anti-apoptotic proteins in these cells.
|Causes vasodilatation by inducing the endothelial nitric oxide synthase and so increasing nitric oxide production.
|VEGFR-A binds many receptors on hematopoietic stem cells (HSCs), monocytes, osteoblasts and neurons; induces HSC mobilization from the bone marrow, monocyte chemo-attraction and osteoblast-mediated bone formation
|Many cytokines including platelet-derived growth factor, basic fibroblast growth factor, the epidermal growth factor and transforming growth factors induce VEGF-A expression in cells.
||Several reports suggest that VEGF-B may modulate cell proliferation and vessel growth. Conditioned medium from transfected cells expressing VEGF-B stimulates DNA synthesis in endothelial cells.
|Shown to play a central role in cardiac development.
||The mature form of VEGF-C induces mitogenesis, migration and survival of ECs
|VEGF-C mRNA transcription is induced in ECs in response to pro-inflammatory cytokines (IL-β).
|Promote lymphatic vessel development and may also contribute to angiogenesis.
||The mature human VEGF-D is mitogenic, angiogenic and lymphogenicin vivo
|Stimulates growth of vascular and lymphatic ECs by signaling through the tyrosine kinase receptors (VEGFR-2, VEGFR-3)
|Promote lymphatic vessel development and may also contribute to angiogenesis.
||Highly specific isoform that acts only on the endocrine gland endothelial cells.
| VEGF-E is a potent angiogenic factor and data strongly indicates that the activation of VEGFR-2 alone can stimulate angiogenesis efficiently.
||Originally identified in the placenta; occurs at low levels in the embryo and adult and has primarily been studied in pathological conditions where it is thought to stimulate angiogenesis in coordination with VEGF-A.
Table 1: Types of vascular endothelial growth factors (VEGFs) with evidence demonstrating their involvement in regulating endothelial cells.
VEGF family members interact with three main receptors,
VEGFR-1 (FLt-1), VEGFR-2 (KDR in humans and Flk-1 in mouse)
and VEGFR-3 (Flt4), all tyrosine kinase receptors and members of the
PGDF receptor family. VEGF receptors possess an extracellular
domain consisting of immunoglobulin repeats responsible for VEGF
binding and intracellular tyrosine kinase domains. VEGF binding to its
receptor leads to receptor dimerization and activation of receptor
tyrosine kinases by autophosphorylation. This leads to several biologic
effects on endothelial cells. The VEGF receptor transmembrane
tyrosine kinases, which upon binding of their ligands to the
extracellular domain of the receptor, activate a cascade of downstream
proteins after the dimerization and autophosphorylation of the
intracellular receptor tyrosine kinases. VEGFR-2 appears to be the
main receptor responsible for mediating the proangiogenic effects of
VEGF-A [57,79,80]. VEGF-A and its receptors VEGFR-1 and
VEGFR-2 are expressed early in embryonic development (Table 2).
|Type of VEGFR
||Role in regulating/modulating endothelial cells (ECs)
||Expressed in ECs as well as osteoblasts, monocytes/macrophages, placental trophoblasts, renal mesangial cells and also in some hematopoietic stem cells (HSCs).
|VEGFR-1 expression is upregulated by hypoxia (HIF1 dependent mechanism).
|Has an active functional role and participates in monocyte migration, recruits EC progenitors and increases adhesive properties of natural killer cells.
||Undergoes dimerization and strong ligand-dependent tyrosine phosphorylation in intact cells and results in a mitogenic, chemotactic, and pro-survival signal.
|Y1175 and Y1214 are the two major VEGF-A-dependent autophosphorylation sites in VEGFR-2. However, only autophosphorylation of Y1175 is imperative for VEGF dependent EC proliferation.
|In addition to the ECs, VEGFR-2 is also expressed on neuronal cells, osteoblasts, megakaryocytes and HSCs.
|It is down-regulated in the blood vascular ECs, and is again up-regulated in angiogenic blood vessels.
|Sequestration of VEGF-A results in down-regulation of VEGFR-2 and in apoptotic death of some capillary endothelial cells in vivo.
|It is an early marker of endothelial and hematopoietic precursor cells in blood islands.
||Recently shown to be strongly modulated by Notch upregulating angiogenesis in absence of VEGF-VEGFR2 signalling.
|VEGFR-3 is up-regulated on blood vascular ECs in pathologic conditions such as in vascular tumors and in the periphery of solid tumors.
|Widely distributed in vascular tumors and can be considered as a marker of endothelial cell differentiation of vascular neoplasms.
|is down-regulated in vivo at sites of endothelial cell–pericyte/smooth muscle cell contacts; suggesting that VEGFR-3 signaling is important in nascent blood vessels, and it becomes redundant as the vessels mature. In humans, VEGFR-3 expression was upregulated in blood vessel endothelium in chronic inflammatory wounds.
Table 2: An overview of vascular endothelial growth factor receptors and their roles in regulating endothelial cells.
Notch signaling: In addition to the VEGF receptor tyrosine kinases
and their ligands, several recent studies demonstrate the importance of
Notch signalling components such as ligands Dll4 (Delta-like ligand 4),
Jagged-1 and Notch1 in EC specification during formation of a
functional vascular network [96-99]. In mammals there are 5 DSL
(Delta Serrate Lag-2) ligands: Delta-like 1 (Dll1), Delta-like 3 (Dll3),
Delta-like 4 (Dll4), Jagged-1 (Jag1) and Jagged-2 (Jag2). These ligands
are type1 cell-surface proteins with multiple tandem epidermal growth
factor (EGF) repeats in their extracellular domains (ECDs). DSL
ligands bind to Notch receptors, which are large, single pass, type1
transmembrane receptors. There are 4 known Notch receptors, Notch1
to Notch4. Binding of a DSL ligand to the ECD of the Notch receptor
(NECD) triggers a series of proteolytic cleavages of Notch, first by a
member of the disintegrin and metalloproteases (ADAM) family
within the juxta-membrane region, followed by γ-secretase within the
transmembrane domain (Table 3). The Notch receptors, ligands, and
several signaling pathway components have been identified in
endothelial cells in vitro and in vivo , during development and tumor
||Pathway component expressed by ECs
||Notch1 and Notch4
||DSL ligands Dll1, Dll4, Jag1 and Jag2
|Key Notch signaling components
||Rbpj, Hey1, Hey2, Maml1, Numb and Nrarp
Table 3: Notch pathway components expressed in endothelial cells.
Functional studies using gene targeting in mice, mutagenesis and
knockdown in zebrafish, and biochemical analysis in cultured
endothelial cells have demonstrated that Notch signaling plays a fundamental role in many aspects of endothelial cell biology during
angiogenesis  (Table 4).
||Notch component(s) involved
|Tip/stalk cell specification
|Matrix production/assembly and cell adhesion
Table 4: Evidence for the role of Notch components involved in endothelial cell function.
EC phenotypes: Interplay between VEGF and Notch signalling in
regulating EC sprouting. An exciting breakthrough within angiogenic
research in the past decade has been the identification of different EC
phenotypes with different cellular fate specifications that are key in
forming a vessel branch . Leading the trail are ‘tip cells’ which
sense and respond to guidance cues. ‘Stalk cells’ follow behind the tip
cells and elongate the stalk of the sprout by proliferating, forming
junctions, modulating the extracellular matrix and forming a lumen.
‘Phalynx cells’, the most quiescent of the ECs, line vessels once new
vessel branches have formed. These cells form a monolayer, are covered
by pericytes, attached via tight junctions, and strongly held by a robust
basement membrane. Phalynx cells are engaged in optimizing blood
flow, tissue perfusion and oxygenation [123-125].
Specification of ECs into tip and stalk cells bearing different
morphologies and functional properties is central to sprouting
initiation [113,126]. Vessel networks, while expanding, require ECs to
undergo frequent cycles of sprouting and branching. This results in
dynamic transitions between the two cell phenotypes [113,126]. Tip
cells express high levels of Dll4, platelet derived growth factor-b
(PDGF-b), unc-5 homolog b (UNC5b), VEGFR 2/3 and has low levels
of Notch signalling activity [98,99,103,127,128]. Stalk cells produce
fewer filopodia, are more proliferative, form tubes, branches and a
vascular lumen, establish junctions with neighbouring cells and
synthesise basement membrane components [113,129]. Tip cell
migration depends on a VEGF gradient migrating outward from
parent vessel whereas stalk cell proliferation is regulated by VEGF
concentration [127,130]. VEGF stimulates tip cell induction and
filopodia formation via VEGFR2 (abundant on filopodia), whereas
VEGFR2 blockade is associated with sprouting defects . VEGFR1
expression is induced by Notch signalling to reduce VEGF ligand
availability preventing tip cell outward migration. VEGFR1 is
predominantly (Figure 2) expressed in stalk cells and is involved in
guidance and limiting tip cell formation. Loss of VEGFR1 results in
increased sprouting and vascularization [131,132].
Figure 2: Islet sprout monitoring in single human islets in time lapse
Notch appears to act as a negative feedback mechanism to regulate
VEGF signaling. This regulation may explain the observation that
decreased VEGFR-2 allows for local differentiation of endothelial tip
cells prior to sprout initiation with VEGF action on tip cells leading to
increased Dll4 expression and activation of Notch signaling, which in
turn downregulates VEGFR-2 in neighboring stalk cells . Tip cells
with higher VEGFR-2 expression will, therefore, readily respond to
VEGF while stalk cells with fewer receptors will be less responsive.
Interestingly, tip cells do not proliferate in response to VEGF, but
rather form filopodia and migrate in the direction of the VEGF
gradient. It is the stalk endothelial cells of the growing capillary branch
that proliferate .
In mouse and zebrafish angiogenesis, VEGFR3 is strongly expressed
in the leading tip cell and is downregulated by Notch signalling in the
stalk cell [98,133]. Notch1 and Notch4 and the three Notch ligands JAG-1, Dll1 and Dll4 are expressed in ECs for the induction of arterial
cell fate and for the selection of endothelial tip and stalk cells during
sprouting angiogenesis . Activation of Notch signalling reduces
while its loss induces sprouting. Notch-1 deficient ECs adopt tip cell
characteristics [97,98,129] whereas in stalk cells, activation of Notch by
Dll4 leads to downregulation of VEGFR-2 and -3 [101,135]. Cells
dynamically compete for tip position utilizing differential VEGFR
levels, as cells with higher VEGFR signalling produces more Dll4 and
therefore inhibit their neighbouring cells. VEGF has been shown to
induce the expression of Dll4 and Notch signaling . Elevated Dll4
and VEGFR-2 expression was detected in tip cells compared to
neighboring stalk cells . Blockage of VEGF, in animal models,
caused a decrease of Dll4 in vessels and inhibited sprouting 
whereas administration of VEGF induced Dll4 expression . Notch
signaling also influences VEGF receptor expression, leading to the
downregulation of VEGFR-2, as evidenced by decreased VEGFR-2
levels after Notch activation in ECs and in Dll4-deficient mice
[99,109]. Endothelial Notch activation regulates the expression of
different VEGFRs (VEGFR1, 2, and 3) as well as the co-receptor Nrp1
[46,93,97,98,103,114,115,137]. Dll4 activates Notch in adjacent cells,
which suppresses the expression of VEGF receptors and thereby
restrains endothelial sprouting and proliferation [98,99,113,138].
Notch activation in HUVECS leads to VEGFR1 mRNA induction
[120,139]. In contrast, VEGFR2 and Nrp1 mRNA is markedly reduced
by Notch activation in HUVECs [137,140,141], indicating that Notch
signaling is able to regulate how the ECs respond to VEGF. The Notch
and VEGF signaling appear to be intimately associated in
angiogenesis. It has been shown that Notch signalling acts downstream
of the VEGF pathway during physiological and pathological
angiogenesis [115,140,142-144], suggesting that VEGF pathway
controls expression of different Notch components (Table 5).
||Recently identified for sprouting angiogenesis
|MEF2 transcription factors
|Foxo1 transcription factor
|ROS and redox events
Table 5: Novel regulators recently identified to play a role in angiogenesis (ECs/VEGF/Notch pathways).
Conclusions and Future Perspectives
Significant progress has been made in our understanding of
importance of angiogenesis in health and disease but our
understanding of coordinated events that result in vessel branching
and vessel inosculation remains incomplete. We are just beginning to appreciate the interplay of other signalling pathways such as Wnt and
BMP in regulating vessel sprouting. Angiogenesis is a complex, multistep
process. Key to this process are ECs, which are pivotal to sprouting
angiogenesis and have been implicated in many diseases [60,161-163].
It has been shown that EC proliferative capacities can be stimulated by
various inducers [41,42,164,165]. A variety of in vivo and in vitro models for understanding EC behaviour during angiogenesis at the
cellular level have been derived from systems such as rabbit cornea
, developing mouse retina , intersegmental vessel growth in
zebrafish  and using ECs embedded in collagen or fibrin gels
In the last two decades, focus has been paramount on the study of
human pancreatic islets, its isolation techniques and in improving islet
yield and function because of it critical involvement in debilitating
diseases such as Type-1 diabetes and chronic pancreatitis. The dense
vasculature within the pancreas is an important determinant in the
physiology and disease of islets. The pancreatic islets is an ideal model
‘tissue’ to learn more about microvasculature and in this context the
study of ECs within islets has potential benefits. The islet EC model
represents an excellent platform to better understand molecular
mechanisms associated with vessel sprouts, an important but greatly
understudied area within islet research. Crosstalk of ECs with other
islet cells, such as the β-cells has been evaluated [171-175] particularly
in increasing β-cell mass and thereby insulin production. Moreover, a
number of factors which may potentially improve islet transplantation involve ECs. Vascular ECs of the embryonic aorta have been shown to
induce the development of endocrine cells from pancreatic epithelium
in mouse [176,177] and overexpression of VEGF-A in transplanted
mouse islets was shown to improve insulin secretion and blood glucose
regulation in recipient mice [165,178]. Utilizing intra-islet ECs as a
model to better understand mechanisms associated with sprouting
angiogenesis is likely to generate exciting new hypotheses and offer
new insights of how transplanted islets can reestablish vasculature
more efficiently and successfully.
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